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Liskova V, Chovancova B, Galvankova K, Klena L, Matyasova K, Babula P, Grman M, Rezuchova I, Bartosova M, Krizanova O. Slow Sulfide Donor GYY4137 Increased the Sensitivity of Two Breast Cancer Cell Lines to Paclitaxel by Different Mechanisms. Biomolecules 2024; 14:651. [PMID: 38927055 PMCID: PMC11202087 DOI: 10.3390/biom14060651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/22/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Paclitaxel (PTX) is a chemotherapeutic agent affecting microtubule polymerization. The efficacy of PTX depends on the type of tumor, and its improvement would be beneficial in patients' treatment. Therefore, we tested the effect of slow sulfide donor GYY4137 on paclitaxel sensitivity in two different breast cancer cell lines, MDA-MB-231, derived from a triple negative cell line, and JIMT1, which overexpresses HER2 and is resistant to trastuzumab. In JIMT1 and MDA-MB-231 cells, we compared IC50 and some metabolic (apoptosis induction, lactate/pyruvate conversion, production of reactive oxygen species, etc.), morphologic (changes in cytoskeleton), and functional (migration, angiogenesis) parameters for PTX and PTX/GYY4137, aiming to determine the mechanism of the sensitization of PTX. We observed improved sensitivity to paclitaxel in the presence of GYY4137 in both cell lines, but also some differences in apoptosis induction and pyruvate/lactate conversion between these cells. In MDA-MB-231 cells, GYY4137 increased apoptosis without affecting the IP3R1 protein, changing the morphology of the cytoskeleton. A mechanism of PTX sensitization by GYY4137 in JIMT1 cells is distinct from MDA-MB-231, and remains to be further elucidated. We suggest different mechanisms of action for H2S on the paclitaxel treatment of MDA-MB-231 and JIMT1 breast cancer cell lines.
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Affiliation(s)
- Veronika Liskova
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Barbora Chovancova
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Kristina Galvankova
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Ladislav Klena
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Katarina Matyasova
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Petr Babula
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00 Brno, Czech Republic;
| | - Marian Grman
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
| | - Ingeborg Rezuchova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovakia; (I.R.); (M.B.)
| | - Maria Bartosova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovakia; (I.R.); (M.B.)
| | - Olga Krizanova
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.L.); (K.G.); (L.K.); (M.G.)
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00 Brno, Czech Republic;
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Roque DM, Siegel ER, Buza N, Bellone S, Silasi DA, Huang GS, Andikyan V, Clark M, Azodi M, Schwartz PE, Rao GG, Reader JC, Hui P, Tymon-Rosario JR, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Ratner E, Santin AD. Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer. Br J Cancer 2022; 126:1695-1703. [PMID: 35149854 PMCID: PMC8853032 DOI: 10.1038/s41416-022-01717-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 12/26/2021] [Accepted: 01/25/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION NCT3093155.
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Affiliation(s)
- Dana M Roque
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eric R Siegel
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Natalia Buza
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Stefania Bellone
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Dan-Arin Silasi
- Division of Gynecologic Oncology, Mercy Clinic, St. Louis, MO, USA
| | - Gloria S Huang
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Vaagn Andikyan
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Mitchell Clark
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Masoud Azodi
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Peter E Schwartz
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Gautam G Rao
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jocelyn C Reader
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Pei Hui
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | | | - Justin Harold
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Dennis Mauricio
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Burak Zeybek
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Gulden Menderes
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Gary Altwerger
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Elena Ratner
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Alessandro D Santin
- Smilow Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA.
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3
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Lin S, Peng T, Meng Y, Cao C, Gao P, Wu P, Zhi W, Wei Y, Chu T, Liu B, Wei J, Huang X, Ding W, Cheng C. Comparison of one-week versus three-week paclitaxel for advanced pan-carcinomas: systematic review and meta-analysis. Aging (Albany NY) 2022; 14:1959-1982. [PMID: 35218640 PMCID: PMC8908930 DOI: 10.18632/aging.203919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/04/2022] [Indexed: 11/25/2022]
Abstract
Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus three-week treatment) remain contradictory in many randomized controlled trials (RCTs). Here, we performed a comprehensive meta-analysis to measure the efficacy and toxicities of these two dosing regimens. Four databases were systematically retrieved. RCTs comparing two paclitaxel dosing regimens for advanced malignant tumors with assessable outcomes (e.g., overall survival (OS), progression-free survival (PFS), toxicities, response rates) were included. In total, 19 eligible RCTs involving 9 674 patients were included. Meta-analysis of pan-cancers revealed that weekly paclitaxel treatment was more beneficial regarding PFS compared to three-week paclitaxel treatment (hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.82–0.99, P = 0.02). Nevertheless, there was no significant difference in terms of OS between the two dosing regimens (HR = 0.98, 95%CI = 0.91–1.06, P = 0.62) or other tested subgroups. In terms of serious adverse events, grade 3 or 4 (G3/4) neutropenia, G3/4 febrile neutropenia, G3/4 arthritis, and G3/4 alopecia occurred less often under weekly paclitaxel treatment. In summary, Weekly paclitaxel treatment demonstrates better PFS and fewer chemotherapy-induced hematological and non-hematological toxicities compared to the three-week paclitaxel regimen.
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Affiliation(s)
- Shitong Lin
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ting Peng
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yifan Meng
- Department of Gynecologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Canhui Cao
- Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Peipei Gao
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Wu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenhua Zhi
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ye Wei
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tian Chu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Binghan Liu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Juncheng Wei
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoyuan Huang
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wencheng Ding
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cai Cheng
- Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Sharifi-Rad J, Quispe C, Patra JK, Singh YD, Panda MK, Das G, Adetunji CO, Michael OS, Sytar O, Polito L, Živković J, Cruz-Martins N, Klimek-Szczykutowicz M, Ekiert H, Choudhary MI, Ayatollahi SA, Tynybekov B, Kobarfard F, Muntean AC, Grozea I, Daştan SD, Butnariu M, Szopa A, Calina D. Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3687700. [PMID: 34707776 PMCID: PMC8545549 DOI: 10.1155/2021/3687700] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022]
Abstract
Paclitaxel is a broad-spectrum anticancer compound, which was derived mainly from a medicinal plant, in particular, from the bark of the yew tree Taxus brevifolia Nutt. It is a representative of a class of diterpene taxanes, which are nowadays used as the most common chemotherapeutic agent against many forms of cancer. It possesses scientifically proven anticancer activity against, e.g., ovarian, lung, and breast cancers. The application of this compound is difficult because of limited solubility, recrystalization upon dilution, and cosolvent-induced toxicity. In these cases, nanotechnology and nanoparticles provide certain advantages such as increased drug half-life, lowered toxicity, and specific and selective delivery over free drugs. Nanodrugs possess the capability to buildup in the tissue which might be linked to enhanced permeability and retention as well as enhanced antitumour influence possessing minimal toxicity in normal tissues. This article presents information about paclitaxel, its chemical structure, formulations, mechanism of action, and toxicity. Attention is drawn on nanotechnology, the usefulness of nanoparticles containing paclitaxel, its opportunities, and also future perspective. This review article is aimed at summarizing the current state of continuous pharmaceutical development and employment of nanotechnology in the enhancement of the pharmacokinetic and pharmacodynamic features of paclitaxel as a chemotherapeutic agent.
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Affiliation(s)
- Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | - Jayanta Kumar Patra
- Research Institute of Biotechnology & Medical Converged Science, Dongguk University, Goyangsi, Republic of Korea
| | - Yengkhom Disco Singh
- Department of Post-Harvest Technology, College of Horticulture and Forestry, Central Agricultural University, Pasighat, 791102 Arunachal Pradesh, India
| | - Manasa Kumar Panda
- Environment and Sustainability Department, CSIR-Institute of Minerals and Materials Technology, Bhubaneswar, 751013 Odisha, India
| | - Gitishree Das
- Research Institute of Biotechnology & Medical Converged Science, Dongguk University, Goyangsi, Republic of Korea
| | - Charles Oluwaseun Adetunji
- Applied Microbiology, Biotechnology and Nanotechnology Laboratory, Department of Microbiology, Edo University Iyamho, PMB 04, Auchi, Edo State, Nigeria
| | - Olugbenga Samuel Michael
- Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Osun State, Nigeria
| | - Oksana Sytar
- Department of Plant Biology Department, Institute of Biology, Taras Shevchenko National University of Kyiv, Kyiv 01033, Ukraine
- Department of Plant Physiology, Slovak University of Agriculture, Nitra 94976, Slovakia
| | - Letizia Polito
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Jelena Živković
- Institute for Medicinal Plants Research “Dr. Josif Pančić”, Tadeuša Košćuška 1, 11000 Belgrade, Serbia
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal
| | - Marta Klimek-Szczykutowicz
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Halina Ekiert
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Muhammad Iqbal Choudhary
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Seyed Abdulmajid Ayatollahi
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
- Department of Pharmacognosy and Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bekzat Tynybekov
- Department of Biodiversity of Bioresources, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Farzad Kobarfard
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ana Covilca Muntean
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Ioana Grozea
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
- Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
| | - Monica Butnariu
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Agnieszka Szopa
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Hsu MY, Hsieh CH, Huang YT, Chu SY, Chen CM, Lee WJ, Liu SJ. Enhanced Paclitaxel Efficacy to Suppress Triple-Negative Breast Cancer Progression Using Metronomic Chemotherapy with a Controlled Release System of Electrospun Poly-d-l-Lactide-Co-Glycolide (PLGA) Nanofibers. Cancers (Basel) 2021; 13:cancers13133350. [PMID: 34283075 PMCID: PMC8268060 DOI: 10.3390/cancers13133350] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Treatment of metastatic triple-negative breast cancer (TNBC) relies on chemotherapy. To improve the efficacy of chemotherapy and avoid systemic toxicity, metronomic chemotherapy using continuous administration of low-dose chemotherapy could be a solution. The paclitaxel-loaded PLGA nanofibers allow for continuous and prolonged drug release, which is compatible with the concept of metronomic chemotherapy. The animal study revealed that the strategy successfully inhibited the growth of the primary tumor and distant metastasis without sarcopenia. These data offer new insights into the role of drug-loaded nanofibers in the treatment of metastatic TNBC. Abstract Triple-negative breast cancer (TNBC) is highly aggressive and responds poorly to conventional chemotherapy. The challenge of TNBC therapy is to maximize the efficacies of conventional chemotherapeutic agents and reduce their toxicities. Metronomic chemotherapy using continuous low-dose chemotherapy has been proposed as a new treatment option, but this approach is limited by the selection of drugs. To improve antitumor therapeutic effects, we developed electrospun paclitaxel-loaded poly-d-l-lactide-co-glycolide (PLGA) nanofibers as a topical implantable delivery device for controlled drug release and site-specific treatment. The subcutaneously implanted paclitaxel-loaded nanofibrous membrane in mice was compatible with the concept of metronomic chemotherapy; it significantly enhanced antitumor activity, inhibited local tumor growth, constrained distant metastasis, and prolonged survival compared with intraperitoneal paclitaxel injection. Furthermore, under paclitaxel-loaded nanofiber treatment, systemic toxicity was low with a persistent increase in lean body weight in mice; in contrast, body weight decreased in other groups. The paclitaxel-loaded nanofibrous membranes provided sustained drug release and site-specific treatment by directly targeting and changing the tumor microenvironment, resulting in low systemic toxicity and a significant improvement in the therapeutic effect and safety compared with conventional chemotherapy. Thus, metronomic chemotherapy with paclitaxel-loaded nanofibrous membranes offers a promising strategy for the treatment of TNBC.
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Affiliation(s)
- Ming-Yi Hsu
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan; (M.-Y.H.); (Y.-T.H.); (S.-Y.C.); (C.-M.C.)
- Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Cheng-Hsien Hsieh
- Department of Emergency Medicine, En-Chu-Kong Hospital, New Taipei City 23741, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Ting Huang
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan; (M.-Y.H.); (Y.-T.H.); (S.-Y.C.); (C.-M.C.)
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Sung-Yu Chu
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan; (M.-Y.H.); (Y.-T.H.); (S.-Y.C.); (C.-M.C.)
| | - Chien-Ming Chen
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan; (M.-Y.H.); (Y.-T.H.); (S.-Y.C.); (C.-M.C.)
| | - Wei-Jiunn Lee
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11695, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (W.-J.L.); (S.-J.L.); Tel.: +886-2-2930-7930 (ext. 2551/2547) (W.-J.L.); +886-3-2118166 (S.-J.L.)
| | - Shih-Jung Liu
- Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Orthopedic Surgery, Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan
- Correspondence: (W.-J.L.); (S.-J.L.); Tel.: +886-2-2930-7930 (ext. 2551/2547) (W.-J.L.); +886-3-2118166 (S.-J.L.)
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6
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Andleeb F, Katta N, Gruslova A, Muralidharan B, Estrada A, McElroy AB, Ullah H, Brenner AJ, Milner TE. Differentiation of Brain Tumor Microvasculature From Normal Vessels Using Optical Coherence Angiography. Lasers Surg Med 2021; 53:1386-1394. [PMID: 34130353 DOI: 10.1002/lsm.23446] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 05/23/2021] [Accepted: 05/27/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND OBJECTIVES Despite rapid advances and discoveries in medical imaging, monitoring therapeutic efficacy for malignant gliomas and monitoring tumor vasculature remains problematic. The purpose of this study is to utilize optical coherence angiography for vasculature characterization inside and surrounding brain tumors in a murine xenograft brain tumor model. Features included in our analysis include fractional blood volume, vessel tortuosity, diameter, orientation, and directionality. STUDY DESIGN/MATERIALS AND METHODS In this study, five tumorous mice models at 4 weeks of age were imaged. Human glioblastoma cells were injected into the brain and allowed to grow for 4 weeks and then imaged using optical coherence tomography. RESULTS Results suggest that blood vessels outside the tumor contain a greater fractional blood volume as compared with vessels inside the tumor. Vessels inside the tumor are more tortuous as compared with those outside the tumor. Results indicate that vessels near the tumor margin are directed inward towards the tumor while normal vessels show a more random orientation. CONCLUSION Quantification of vascular microenvironments in brain gliomas can provide functional vascular parameters to aid various diagnostic and therapeutic studies. © 2021 Wiley Periodicals LLC.
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Affiliation(s)
- Farah Andleeb
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA.,Biophotonics Research Lab, Institute of Physics, The Islamia University, Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan.,Department of Physics, Government Sadiq College Women University Bahawalpur, Bahwalpur, Punjab, 63100, Pakistan
| | - Nitesh Katta
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA
| | - Aleksandra Gruslova
- University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
| | - Bharadwaj Muralidharan
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA
| | - Arnold Estrada
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA
| | - Austin B McElroy
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA
| | - Hafeez Ullah
- Biophotonics Research Lab, Institute of Physics, The Islamia University, Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan
| | - Andrew J Brenner
- University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
| | - Thomas E Milner
- Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA
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7
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Mollaei M, Hassan ZM, Khorshidi F, Langroudi L. Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells? Transl Oncol 2021; 14:101056. [PMID: 33684837 PMCID: PMC7938256 DOI: 10.1016/j.tranon.2021.101056] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
Chemotherapeutic drugs kill cancer cells or control their progression all over the patient's body, while radiation- and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresistance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conventional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.
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Affiliation(s)
- Mojtaba Mollaei
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran.
| | | | - Fatemeh Khorshidi
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran; Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Langroudi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Rumman M, Buck S, Polin L, Dzinic S, Boerner J, Winer IS. ONC201 induces the unfolded protein response (UPR) in high- and low-grade ovarian carcinoma cell lines and leads to cell death regardless of platinum sensitivity. Cancer Med 2021; 10:3373-3387. [PMID: 33932119 PMCID: PMC8124100 DOI: 10.1002/cam4.3858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/06/2020] [Accepted: 12/18/2020] [Indexed: 11/09/2022] Open
Abstract
Objectives Treatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA. Methods Cisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy. Results ONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433). Conclusions Our findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA.
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Affiliation(s)
- Marufa Rumman
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Steven Buck
- Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA
| | - Lisa Polin
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Sijana Dzinic
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Julie Boerner
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Ira S Winer
- Division of Gynecologic Oncology, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
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Mansouri A, McGregor N, Dunn R, Dobbie S, Holmes J, Collins L, Nicum S. Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer (OCTOVA): a study protocol. BMJ Open 2021; 11:e041463. [PMID: 33452192 PMCID: PMC7813404 DOI: 10.1136/bmjopen-2020-041463] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/02/2020] [Accepted: 11/15/2020] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Patients relapsing within 12 months of platinum-based chemotherapy usually have a poorer response to subsequent treatments. To date, extensive research into the mechanism of resistance to platinum agents in the treatment of ovarian cancer has not resulted in improved responses or longer survival. Further experimental work and clinical trials with novel agents are therefore justified to address this unmet need.Patients with ovarian, fallopian tube or primary peritoneal cancer that has relapsed within 12 months of platinum-based chemotherapy will be randomised with stratification for BReast CAncer gene (BRCA) status, prior poly (ADP-ribose) polymerase (PARP) exposure and prior antiangiogenic therapy into weekly paclitaxel (chemotherapy), olaparib or the combination of cediranib and olaparib. They will be followed until disease progression or unacceptable toxicity develops. Our trial design permits two investigations. We will compare the efficacy and tolerability of single-agent olaparib with weekly paclitaxel. We will also compare the efficacy and tolerability of olaparib with the combination of olaparib and cediranib. The required sample size of 138 participants (46 per arm) was calculated using a 20% one-sided type I error, 80% power and 15% dropout rate. Recruitment will last 34 months with a follow-up of 18 months. METHODS AND ANALYSIS ETHICS AND DISSEMINATION: This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency Clinical Trials Authorisation. Approval to conduct the study was obtained from the responsible authority before beginning the study. The sponsor will retain ownership of all data arising from the trial. We aim to publish this research in a specialist peer-reviewed scientific journal on study completion. EudraCT number: 2016-000559-28, ethics reference number: 16/LO/2150. TRIAL REGISTRATION NUMBER ISRCTN: ISRCTN14784018, clinicaltrials.gov: NCT03117933; Pre-results.
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Affiliation(s)
- Anita Mansouri
- Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Naomi McGregor
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, UK
| | - Rachel Dunn
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, UK
| | - Sam Dobbie
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, UK
| | - Jane Holmes
- Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Linda Collins
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, UK
| | - Shibani Nicum
- Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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10
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Zhang M, Yang R, Zhou Z, Li C, Liu Y, Li W, Pan J, Sun M, Qian C. Tissue-Specific Regulation of Reactive Oxygen Species by an ATP-Responsive Nanoregulator Enhances Anticancer Efficacy and Reduces Anthracycline-Induced Cardiotoxicity. ACS APPLIED BIO MATERIALS 2020; 3:8000-8011. [DOI: 10.1021/acsabm.0c01049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Minghua Zhang
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Ruoxi Yang
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Zhanwei Zhou
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Chenzi Li
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yadong Liu
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Wei Li
- Division of Nephrology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Jiacheng Pan
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Minjie Sun
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Chenggen Qian
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
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Madariaga A, Garg S, Bruce JP, Thiryayi S, Mandilaras V, Rath P, Oza AM, Dhani NC, Cescon DW, Lee YC, Chen E, Wang L, Clarke B, Lheureux S. Biomarkers of outcome to weekly paclitaxel in epithelial ovarian cancer. Gynecol Oncol 2020; 159:539-545. [PMID: 32912664 DOI: 10.1016/j.ygyno.2020.08.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 08/27/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE We sought to evaluate the role of intrinsic chromosomal aberrations in determining favorable outcome to weekly paclitaxel (WP) in patients with epithelial ovarian cancer (EOC). METHODS We evaluated the common genomic aberrations of two patients with EOC and exceptional WP response in the GENIUS study (NCT03740503). We then searched for potential markers of unusual outcomes to WP in a validation cohort. We performed shallow whole genome sequencing (sWGS) in the tumor tissue of women with EOC considered as short-responders (SR; progression with ≤3 cycles) and long-responders (LR; response at ≥8 cycles) to WP monotherapy. RESULTS We identified two women with exceptional response to WP, lasting over four years, who shared chromosome 8 gain as a common genomic aberration. In order to validate our findings, we reviewed 188 patients with EOC treated with WP and selected 61 women (39 SR, 22 LR) with unusual responses. By sWGS, there was no differential alterations in the copy number changes in chromosome 8, or in genes related to angiogenesis, tubulin superfamily, cell-cycle, apoptosis and paclitaxel metabolism or transportation pathways. Amongst the LR group, we identified six exceptionally long responders (ExLR), with responses lasting over a year. In an exploratory analysis, there was increased amplification of angiogenesis (VEGFB, MMP9), tubulin superfamily (TSC2) and apoptosis related genes (BCL2L1, BAD) in ExLR compared to SR. We identified one patient with a complete response to WP for over 7 years. Molecular profiling identified unique amplifications in interleukin related genes (CXCR1, CXCR2, IL1A, IL1B), not detected in other patients. CONCLUSION Intrinsic tumor pathways may impact outcome with weekly paclitaxel monotherapy and further investigations are required.
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Affiliation(s)
- Ainhoa Madariaga
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Swati Garg
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jeffrey P Bruce
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Sakinah Thiryayi
- University of Toronto, Toronto, ON, Canada; Division of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Victoria Mandilaras
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Prisni Rath
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Amit M Oza
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Neesha C Dhani
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - David W Cescon
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Yeh Chen Lee
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Eric Chen
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Lisa Wang
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Blaise Clarke
- University of Toronto, Toronto, ON, Canada; Division of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Stephanie Lheureux
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
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12
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Soyama H, Miyamoto M, Matsuura H, Iwahashi H, Kakimoto S, Ishibashi H, Sakamoto T, Hada T, Suminokura J, Takano M. Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine. Cancer Chemother Pharmacol 2020; 85:941-947. [PMID: 32279102 DOI: 10.1007/s00280-020-04070-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/02/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.
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Affiliation(s)
- Hiroaki Soyama
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Morikazu Miyamoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.
| | - Hiroko Matsuura
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideki Iwahashi
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Soichiro Kakimoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroki Ishibashi
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Takahiro Sakamoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Taira Hada
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Jin Suminokura
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Masashi Takano
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
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Eskander RN, Monk BJ. Moving beyond cytotoxic drug dosing in ovarian cancer. Lancet 2019; 394:2043-2045. [PMID: 31791687 DOI: 10.1016/s0140-6736(19)32948-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 11/18/2019] [Indexed: 11/20/2022]
Affiliation(s)
- Ramez N Eskander
- Division of Gynecologic Oncology and Center for Personalized Cancer Therapy, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Diego, Moores Comprehensive Cancer Center, La Jolla, CA 92093, USA.
| | - Bradley J Monk
- Division of Gynecologic Oncology and Center for Personalized Cancer Therapy, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Diego, Moores Comprehensive Cancer Center, La Jolla, CA 92093, USA
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Abstract
OBJECTIVE To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m, administered on day 1, 8, and 15 without day 22). MATERIALS AND METHODS A retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52). RESULTS In the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received ≥6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036). CONCLUSION Our results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer.
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Zou L, Liu X, Li J, Li W, Zhang L, Li J, Zhang J. Tetramethylpyrazine Enhances the Antitumor Effect of Paclitaxel by Inhibiting Angiogenesis and Inducing Apoptosis. Front Pharmacol 2019; 10:707. [PMID: 31293426 PMCID: PMC6603208 DOI: 10.3389/fphar.2019.00707] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 05/31/2019] [Indexed: 01/04/2023] Open
Abstract
Recent published findings have demonstrated the effectiveness of combining molecules from traditional Chinese medicine with chemotherapeutic drugs to treat cancer. Combined administration of these agents can overcome drug-mitigating responses as well as reduce adverse side effects, thereby enhancing the efficacy of the therapy. Tetramethylpyrazine (TMP), an alkaloid monomer from the medicinal herb Ligusticum chuanxiong hort, is known to exert a variety of antitumor effects including inhibition of tumor cell proliferation, metastasis, and drug resistance. In this research, we investigated antitumor effects of TMP combined with paclitaxel (PTX), a frontline chemotherapeutic drug, in vitro and in vivo. Our results indicate that TMP enhances the antitumor effects of PTX in ovarian cancer A2780 and SKOV3 cells. Furthermore, we found that combined treatment of TMP and PTX suppressed angiogenesis by inhibiting both ERK1/2 and Akt pathways and promoted apoptosis of tumor cells compared to TMP or PTX treatment alone. Moreover, TMP augmented the antitumor effects of PTX in ovarian cancer A2780 xenograft mouse models by significantly decreasing tumor burden and partially decreasing the toxicity of PTX, as evidenced by the decreased expression of proliferation and angiogenesis markers as well as the hematoxylin and eosin (H&E) staining and biochemical indexes assay. Overall, our findings provide novel mechanistic insight into the efficacy of combining of potent molecules present in traditional Chinese medicine with chemotherapeutic drugs for therapeutic intervention in cancer.
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Affiliation(s)
- Liang Zou
- School of Medicine, Chengdu University, Chengdu, China.,Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Xiaowei Liu
- School of Medicine, Chengdu University, Chengdu, China
| | - Jingjing Li
- Department of Pharmacy and Pharmacology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wei Li
- School of Medicine, Chengdu University, Chengdu, China
| | - Lele Zhang
- School of Medicine, Chengdu University, Chengdu, China
| | - Jian Li
- School of Medicine, Chengdu University, Chengdu, China
| | - Jinming Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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16
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Vrdoljak J, Boban T, Petrić Miše B, Boraska Jelavić T, Bajić Ž, Tomić S, Vrdoljak E. Efficacy and safety of TC dose-dense chemotherapy as first-line treatment of epithelial ovarian cancer: a single-institution retrospective cohort study. Jpn J Clin Oncol 2019; 49:347-353. [PMID: 30796833 DOI: 10.1093/jjco/hyz011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/21/2018] [Accepted: 01/15/2019] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The optimal first-line therapy of advanced ovarian cancer still remains questionable: standard paclitaxel-carboplatin (TC), dose-dense TC, intraperitoneal chemotherapy or TC plus bevacizumab. In this study, we present the real-life results of dose-dense treatment of the single-institution on Caucasian population. METHODS A retrospective cohort study was used on consecutive samples of 74 patients treated with the conventional 3-weekly TC protocol (2008-11) and on 70 treated with TC dose-dense protocol (2012-16). The primary endpoint of this study was overall survival (OS). Secondary endpoints were progression free-survival (PFS) and toxicity. We made adjustments for age, pathohistological type, tumor grade, stage and postoperative residual disease by Cox regression. RESULTS After adjustment for pre-planned clinical and sociodemographic factors, patients treated with dose-dense protocol showed a significantly lower hazard for dying from any cause, than patients treated with conventional protocol (HR = 0.50; 95% CI 0.26-0.98; P = 0.042). Median OS, at 60 months follow-up had not been reached in the dose-dense group, while in the standard treatment group was 48 months (95% CI 33-62). Unadjusted PFS was significantly longer in the dose-dense group (HR = 0.58; 95% CI 0.38-0.88; P = 0.011), but not after the adjustment (P = 0.096). Generally, the level of toxicity was similar in both groups of patients. The need for blood transfusions and usage of filgrastim was significantly higher in the TC dd group. The incidence of neutropenia and thrombocytopenia Grade 3 or 4 were not significantly different in both regimens. CONCLUSIONS Our retrospective study has shown the superior efficacy and comparable toxicity of dose-dense chemotherapy regimen over the conventional regimen in treatment of ovarian cancer on Caucasian population at a single-institution.
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Affiliation(s)
- J Vrdoljak
- University of Split, Medical School, Šoltanska 2, 21000 Split, Croatia
| | - T Boban
- Department of Oncology, Clinical Hospital Center Split, Spinčićeva 1, 21000 Split, Croatia
| | - B Petrić Miše
- Department of Oncology, Clinical Hospital Center Split, Spinčićeva 1, 21000 Split, Croatia
| | - T Boraska Jelavić
- Department of Oncology, Clinical Hospital Center Split, Spinčićeva 1, 21000 Split, Croatia
| | - Ž Bajić
- Scientific Unit, Psychiatric Hospital Sveti Ivan, Jankomir 11, 10000 Zagreb, Croatia
| | - S Tomić
- Department of Pathology, Forensic Medicine and Cytology, Clinical Hospital Split, Spinčićeva 1, 21000 Split, Croatia
| | - E Vrdoljak
- Department of Oncology, Clinical Hospital Center Split, Spinčićeva 1, 21000 Split, Croatia
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Filippi R, Lombardi P, Depetris I, Fenocchio E, Quarà V, Chilà G, Aglietta M, Leone F. Rationale for the use of metronomic chemotherapy in gastrointestinal cancer. Expert Opin Pharmacother 2018; 19:1451-1463. [PMID: 30161003 DOI: 10.1080/14656566.2018.1512585] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Metronomic chemotherapy (mCT) is endowed with various properties, ranging from antiangiogenic to immunomodulation, and may revert tumor resistance to conventional drug administration. A variety of antineoplastic agents displayed activity when administered with metronomic schedules in preclinical models of gastrointestinal cancers. However, most of the field is still unexplored. AREAS COVERED Herein, the authors review the existing literature from PubMed, concerning the use of mCT in gastrointestinal oncology. EXPERT OPINION A mounting body of evidence is emerging in support of mCT as a treatment option for gastrointestinal tumors, but the frequent signs of clinical activity inconsistently translate into a benefit for survival. Research in this field should focus on providing high-quality evidence on the safety and efficacy of mCT, with more prospective, comparative trials; identifying the subgroups of patients for whom mCT would be the best approach; establishing standardized protocols based on mCT pharmacokinetics and pharmacodynamics; developing drug activity biomarkers. mCT is also potentially suitable for combinations with targeted antiangiogenic drugs and may be incorporated with conventional administration into dual regimens.
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Affiliation(s)
- Roberto Filippi
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Pasquale Lombardi
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Ilaria Depetris
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Elisabetta Fenocchio
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Virginia Quarà
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Giovanna Chilà
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Massimo Aglietta
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Francesco Leone
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
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18
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Ng T, Phey XY, Yeo HL, Shwe M, Gan YX, Ng R, Ho HK, Chan A. Impact of Adjuvant Anthracycline-Based and Taxane-Based Chemotherapy on Plasma VEGF Levels and Cognitive Function in Breast Cancer Patients: A Longitudinal Study. Clin Breast Cancer 2018; 18:e927-e937. [PMID: 29705024 DOI: 10.1016/j.clbc.2018.03.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 03/31/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) has been shown to induce neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that chemotherapy reduces circulating VEGF levels and leads to cognitive decline among patients. This multicenter longitudinal study aimed to evaluate the impact of chemotherapy on VEGF levels and the association between VEGF levels and cognitive function. PATIENTS AND METHODS A total of 145 early-stage breast cancer patients were recruited and assessed before chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). At each time point, plasma VEGF levels were assessed using a multiplex immunoassay. Cognitive function was assessed using both Functional Assessment of Cancer Therapy-Cognitive Function, Version 3 (FACT-Cog), and Headminder (a computerized, web-based neuropsychologic battery). RESULTS Generally, we observed higher-than-baseline plasma VEGF levels after the start of chemotherapy (P < .001). Among patients receiving anthracycline-based chemotherapy, the median plasma VEGF levels were significantly higher at T2 (T2: 37.3 pg/mL vs. T1: 21.3 pg/mL; P < .001) and T3 (T3: 35.5 pg/mL vs. T1: 21.3 pg/mL; P < .001) than at baseline. Plasma VEGF levels were not associated with chemotherapy-associated cognitive impairment. CONCLUSION Breast cancer patients experience an increasing trend in plasma VEGF levels during chemotherapy, and the regimen types may have a differential effect on circulating VEGF levels. Furthermore, changes in plasma VEGF levels during chemotherapy were not associated with cognitive impairment. VEGF may play a minor role in mediating the occurrence of chemotherapy-associated cognitive impairment.
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Affiliation(s)
- Terence Ng
- Department of Pharmacy, National University of Singapore, Singapore
| | - Xiang Yun Phey
- Department of Pharmacy, National University of Singapore, Singapore
| | - Hui Ling Yeo
- Department of Pharmacy, National University of Singapore, Singapore
| | - Maung Shwe
- Department of Pharmacy, National University of Singapore, Singapore
| | - Yan Xiang Gan
- Department of Pharmacy, National University of Singapore, Singapore
| | - Raymond Ng
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Graduate Medical School Singapore, Singapore
| | - Han Kiat Ho
- Department of Pharmacy, National University of Singapore, Singapore
| | - Alexandre Chan
- Department of Pharmacy, National University of Singapore, Singapore; Oncology Pharmacy, National Cancer Centre Singapore, Singapore; Duke-NUS Graduate Medical School Singapore, Singapore.
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19
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Biziota E, Mavroeidis L, Hatzimichael E, Pappas P. Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation. Cancer Lett 2016; 400:243-251. [PMID: 28017892 DOI: 10.1016/j.canlet.2016.12.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 01/09/2023]
Abstract
Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule.
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Affiliation(s)
- Eirini Biziota
- Department of Medical Oncology, University Hospital of Evros, Alexandroupolis, 68 100, Greece.
| | - Leonidas Mavroeidis
- Department of Pharmacology, Faculty of Medicine, School of Life Sciences, University of Ioannina, Ioannina, 451 10, Greece.
| | | | - Periklis Pappas
- Department of Pharmacology, Faculty of Medicine, School of Life Sciences, University of Ioannina, Ioannina, 451 10, Greece.
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20
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Cannita K, Paradisi S, Cocciolone V, Bafile A, Rinaldi L, Irelli A, Lanfiuti Baldi P, Zugaro L, Manetta R, Alesse E, Ricevuto E, Ficorella C. New schedule of bevacizumab/paclitaxel as first-line therapy for metastatic HER2-negative breast cancer in a real-life setting. Cancer Med 2016; 5:2232-9. [PMID: 27416882 PMCID: PMC5055157 DOI: 10.1002/cam4.803] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 05/16/2016] [Accepted: 05/20/2016] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first-line treatment of unselected, HER2-negative, metastatic breast cancer (MBC) patients, in a real-life setting. Thirty-five patients (median age 56 years, range 40-81) with HER2-negative MBC were treated with paclitaxel (70 mg/m(2) ) dd 1,8,15 q21 (60 mg/m(2) if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty-two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple-negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow-up of 13 months (range 1-79 months), the median progression-free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real-life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.
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Affiliation(s)
- Katia Cannita
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.
| | - Stefania Paradisi
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Valentina Cocciolone
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.,Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - Lucia Rinaldi
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Azzurra Irelli
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Paola Lanfiuti Baldi
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Luigi Zugaro
- Division of Radiology, S. Salvatore Hospital, L'Aquila, Italy
| | - Rosa Manetta
- Division of Radiology, S. Salvatore Hospital, L'Aquila, Italy
| | - Edoardo Alesse
- Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Enrico Ricevuto
- Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.,Oncology Network ASL1 Abruzzo, UOSD Oncology Territorial Care, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Corrado Ficorella
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.,Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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21
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Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, DiSilvestro PA, Rubin SC, Martin LP, Davidson SA, Huh WK, O'Malley DM, Boente MP, Michael H, Monk BJ. Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. N Engl J Med 2016; 374:738-48. [PMID: 26933849 PMCID: PMC5081077 DOI: 10.1056/nejmoa1505067] [Citation(s) in RCA: 272] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).
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Affiliation(s)
- John K Chan
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Mark F Brady
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Richard T Penson
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Helen Huang
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Michael J Birrer
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Joan L Walker
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Paul A DiSilvestro
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Stephen C Rubin
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Lainie P Martin
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Susan A Davidson
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Warner K Huh
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - David M O'Malley
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Matthew P Boente
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Helen Michael
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
| | - Bradley J Monk
- From the California Pacific-Palo Alto Medical Foundation, Sutter Cancer Research Institute, San Francisco (J.K.C.); NRG Oncology-Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY (M.F.B., H.H.); Massachusetts General Hospital, Boston (R.T.P., M.J.B.); University of Oklahoma, Oklahoma City (J.L.W.); Women and Infants Hospital, Providence, RI (P.A.D.S.); University of Pennsylvania (S.C.R.) and Fox Chase Cancer Center (L.P.M.) - both in Philadelphia; University of Colorado Cancer Center, Aurora (S.A.D.); University of Alabama at Birmingham, Birmingham (W.K.H.); James Cancer Center, Ohio State University, Columbus (D.M.O.); Minnesota Oncology/Hematology-Oncology Service, Edina (M.P.B.); Indiana University School of Medicine, Carmel (H.M.); and University of Arizona Cancer Center, Creighton University School of Medicine, and St. Joseph's Hospital and Medical Center (B.J.M.) - all in Phoenix
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22
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Development of nanotheranostics against metastatic breast cancer--A focus on the biology & mechanistic approaches. Biotechnol Adv 2015; 33:1897-911. [PMID: 26454168 DOI: 10.1016/j.biotechadv.2015.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/25/2015] [Accepted: 10/05/2015] [Indexed: 12/23/2022]
Abstract
Treatment for metastatic breast cancer still remains to be a challenge since the currently available diagnostic and treatment strategies fail to detect the micro-metastasis resulting in higher mortality rate. Moreover, the lack of specificity to target circulating tumor cells is also a factor. In addition, currently available imaging modalities to identify the secondaries vary with respect to various metastatic anatomic areas and size of the tumor. The drawbacks associated with the existing clinical management of the metastatic breast cancer demands the requirement of multifunctional nanotheranostics, which could diagnose at macro- and microscopic level, target the solid as well as circulating tumor cells and control further progression with the simultaneous evaluation of treatment response in a single platform. However, without the understanding of the biology as well as preferential homing ability of circulating tumor cells at distant organs, it is quite impossible to address the existing challenges in the present diagnostics and therapeutics against the breast cancer metastasis. Hence this review outlines the severity of the problem, basic biology and organ specificity with the sequential steps for the secondary progression of disease followed by the various mechanistic approaches in diagnosis and therapy at different stages.
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23
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Schrading S, Kuhl CK. Breast Cancer: Influence of Taxanes on Response Assessment with Dynamic Contrast-enhanced MR Imaging. Radiology 2015; 277:687-96. [PMID: 26176656 DOI: 10.1148/radiol.2015150006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To prospectively investigate the influence of taxane-containing neoadjuvant chemotherapy (T-NACT) versus non-taxane-containing NACT (NT-NACT) on the contrast material enhancement of breast cancers, benign enhancing lesions (BELs), and background parenchymal enhancement (BPE) at dynamic contrast-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS This institutional review board-approved study was performed in 62 patients with invasive breast cancer who underwent multiagent NACT with (n = 49) or without (n = 13) taxanes between 2008 and 2011. Written informed consent was obtained. Patients underwent dynamic contrast-enhanced MR imaging according to a standardized protocol before and 2 weeks after completing NACT. The percentage reduction of enhancement of breast cancers, BELs, and BPEs was calculated for patients undergoing NT-NACT versus those undergoing T-NACT. Final surgical pathologic results served as standard of reference. Changes in mean enhancement of breast cancers, BELs, and BPEs between the regimens were compared by using the Student t test for unpaired samples; for intraindividual comparison, the Student t test for paired samples was used. RESULTS Similar rates of complete pathologic response were observed after T-NACT and NT-NACT (28 [57.2%] of 49 vs eight [61.5%] of 13). T-NACT was associated with an almost complete suppression of enhancement in not only breast cancers but also BELs and BPE in the same patients, with an average reduction of enhancement of -89.9% ± 9.3, -90.2% ± 11.8, and -91.2% ± 7.5, respectively. After T-NACT, cancers with partial (n = 21) or complete (n = 28) pathologic response exhibited a similar reduction of enhancement (-81.8% ± 17.5 vs -93.9% ± 2.3; P = .22). The reduction of enhancement of cancers after NT-NACT was significantly less pronounced than that after T-NACT (-41.1% ± 22.8 vs 88.1% ± 13.9; P < .0001), and effects on enhancement of BELs and BPE were significantly less pronounced compared with effects on enhancement of cancers in the same women (P < .0001). MR imaging led to an overestimation of response (yielded false-negative results for residual disease) in 66.7% (14 of 21) of patients after T-NACT, versus in 20% (one of five) of patients after NT-NACT. CONCLUSION The reduction of enhancement observed in breast cancers after T-NACT is, in part, unrelated to their oncologic response. MR imaging-detectable effects of taxanes represent a combination of specific antimitotic and nonspecific antiangiogenic effects. This impacts the accuracy with which dynamic contrast-enhanced MR imaging helps predict complete pathologic response to T-NACT. (©) RSNA, 2015 Online supplemental material is available for this article.
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Affiliation(s)
- Simone Schrading
- From the Department of Diagnostic and Interventional Radiology, University of Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Christiane K Kuhl
- From the Department of Diagnostic and Interventional Radiology, University of Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
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Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2015. [PMID: 26137480 DOI: 10.1155/2015/413076] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.
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Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2015. [PMID: 26137480 DOI: 10.1155/2015/413076]+[] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.
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Kampan NC, Madondo MT, McNally OM, Quinn M, Plebanski M. Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2015; 2015:413076. [PMID: 26137480 PMCID: PMC4475536 DOI: 10.1155/2015/413076] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023]
Abstract
Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.
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Affiliation(s)
- Nirmala Chandralega Kampan
- Department of Immunology, Monash University, Level 6, The Alfred, Commercial Road, Melbourne, VIC 3181, Australia
- Gynaeoncology Unit, Royal Women's Hospital, 20 Flemington Road, Parkville, Melbourne, VIC 3052, Australia
| | - Mutsa Tatenda Madondo
- Department of Immunology, Monash University, Level 6, The Alfred, Commercial Road, Melbourne, VIC 3181, Australia
| | - Orla M. McNally
- Gynaeoncology Unit, Royal Women's Hospital, 20 Flemington Road, Parkville, Melbourne, VIC 3052, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Michael Quinn
- Gynaeoncology Unit, Royal Women's Hospital, 20 Flemington Road, Parkville, Melbourne, VIC 3052, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Magdalena Plebanski
- Department of Immunology, Monash University, Level 6, The Alfred, Commercial Road, Melbourne, VIC 3181, Australia
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Molecular mechanism of local drug delivery with Paclitaxel-eluting membranes in biliary and pancreatic cancer: new application for an old drug. Gastroenterol Res Pract 2015; 2015:568981. [PMID: 25983747 PMCID: PMC4423024 DOI: 10.1155/2015/568981] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 10/06/2014] [Accepted: 10/07/2014] [Indexed: 12/31/2022] Open
Abstract
Implantation of self-expanding metal stents (SEMS) is palliation for patients suffering from inoperable malignant obstructions associated with biliary and pancreatic cancers. Chemotherapeutic agent-eluting stents have been developed because SEMS are susceptible to occlusion by tumor in-growth. We reported recently that paclitaxel-eluting SEMS provide enhanced local drug delivery in an animal model. However, little is known about the molecular mechanisms by which paclitaxel-eluting stents attenuate tumor growth. We investigated the signal transduction pathways underlying the antiproliferative effects of a paclitaxel-eluting membrane (PEM) implanted in pancreatic/cholangiocarcinoma tumor bearing nude mice. Molecular and cellular alterations were analyzed in the PEM-implanted pancreatic/cholangiocarcinoma xenograft tumors by Western blot, immunoprecipitation, and immunofluorescence. The quantities of paclitaxel released into the tumor and plasma were determined by liquid chromatography-tandem mass spectroscopy. Paclitaxel from the PEM and its diffusion into the tumor inhibited angiogenesis, which involved suppression of mammalian target of rapamycin (mTOR) through regulation of hypoxia inducible factor (HIF-1) and increased apoptosis. Moreover, implantation of the PEM inhibited tumor-stromal interaction-related expression of proteins such as CD44, SPARC, matrix metalloproteinase-2, and vimentin. Local delivery of paclitaxel from a PEM inhibited growth of pancreatic/cholangiocarcinoma tumors in nude mice by suppressing angiogenesis via the mTOR and inducing apoptosis signal pathway.
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Sun J, Xiao Y, Wang S, Slepian MJ, Wong PK. Advances in Techniques for Probing Mechanoregulation of Tissue Morphogenesis. ACTA ACUST UNITED AC 2015; 20:127-37. [DOI: 10.1177/2211068214554802] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Fung AS, Lee C, Yu M, Tannock IF. The effect of chemotherapeutic agents on tumor vasculature in subcutaneous and orthotopic human tumor xenografts. BMC Cancer 2015; 15:112. [PMID: 25884767 PMCID: PMC4363401 DOI: 10.1186/s12885-015-1091-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 02/19/2015] [Indexed: 01/26/2023] Open
Abstract
Background The growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature. Some chemotherapeutic agents have shown anti-angiogenic properties but there are limited studies of the effect of chemotherapy on tumor vasculature. Here we investigate the effect of paclitaxel, 5-fluorouracil (5-FU) and doxorubicin on tumor vasculature in subcutaneous and orthotopic xenografts in mice. Methods The vascular density and percentage of functional blood vessels were evaluated in subcutaneous A431 human vulvar cancer xenografts, and in subcutaneous and orthotopic MCF-7 human breast cancer xenografts, following single doses of paclitaxel, 5-FU or doxorubicin. Results There was no significant difference in total (CD31+) blood vessels between untreated ectopic and orthotopic MCF-7 tumors, but there was a significantly lower proportion of functional blood vessels in orthotopic tumors. After paclitaxel treatment, there was a decrease in functional tumor vasculature in A431 subcutaneous xenografts, followed by a subsequent rebound. There was a significant decrease in total vascular density on day 12 in A431 tumors following 5-FU or doxorubicin treatment, but no change in the percentage of functional vessels. An increase in functional blood vessels or percentage of functional vasculature was noted in MCF-7 subcutaneous and orthotopic xenografts following chemotherapy treatment. Conclusions There are differences in the vasculature and microenvironment of ectopic and orthotopic xenografts in mice. Anti-tumor effects of chemotherapy may be due, in part, to effects on tumor vasculature and may vary in different tumor models.
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Affiliation(s)
- Andrea S Fung
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, 610 University Avenue, Toronto, ON, M5G 2 M9, Canada.
| | - Carol Lee
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, 610 University Avenue, Toronto, ON, M5G 2 M9, Canada.
| | - Man Yu
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, 610 University Avenue, Toronto, ON, M5G 2 M9, Canada.
| | - Ian F Tannock
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, 610 University Avenue, Toronto, ON, M5G 2 M9, Canada.
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Chang WL, Yu CC, Chen CS, Guh JH. Tubulin-binding agents down-regulate matrix metalloproteinase-2 and -9 in human hormone-refractory prostate cancer cells – a critical role of Cdk1 in mitotic entry. Biochem Pharmacol 2015; 94:12-21. [PMID: 25615907 DOI: 10.1016/j.bcp.2015.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 01/10/2015] [Accepted: 01/13/2015] [Indexed: 12/14/2022]
Abstract
Tubulin is an important target for anticancer therapy. Taxanes and vinca alkaloids are two groups of tubulin-binding agents in cancer chemotherapy. Besides tubulin binding, these groups of agents can also down-regulate protein levels of matrix metalloproteinase (MMP)-2 and -9, two important cancer-associated zinc-dependent endopeptidases in invasion and metastasis. However, the mechanism of action waits to be explored. In this study, protein levels but not mRNA expressions of MMP-2 and -9 were down-regulated by paclitaxel (a microtubule-stabilization agent), vincristine and evodiamine (two tubulin-depolymerization agents). These agents induced an increase of protein expression of cyclin B1, MPM2 (mitosis-specific phosphoprotein) and polo-like kinase (PLK) 1 phosphorylation. The data showed a negative relationship between the levels of mitotic proteins and MMP-2 and -9 expressions. MG132 (a specific cell-permeable proteasome inhibitor) blocked mitotic entry and arrested cell cycle at G2 phase, preventing down-regulation of MMP-2 and -9. Cell cycle synchronization experiments by thymidine block or nocodazole treatment showed that mitotic exit inhibited the down-regulation of MMP-2 and -9, confirming negative relationship between cell mitosis and protein levels of MMP-2 and -9 expressions. Cyclin-dependent kinase (Cdk) 1 is a key kinase in mitotic entry. Knockdown of Cdk1 almost completely inhibited the down-regulation of MMP-2 and -9 induced by tubulin-binding agents. In conclusion, the data suggest that mitotic entry and Cdk1 plays a central role in down-regulation of MMP-2 and -9 protein expressions. Tubulin-binding agents cause mitotic arrest and Cdk1 activation, which may contribute largely to the down-regulation of both MMP-2 and -9 expressions.
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Affiliation(s)
- Wei-Ling Chang
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan; The Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
| | - Chia-Chun Yu
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan
| | - Ching-Shih Chen
- The Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
| | - Jih-Hwa Guh
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan.
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Yang G, Nie P, Kong Y, Sun H, Hou G, Han J. MicroPET imaging of tumor angiogenesis and monitoring on antiangiogenic therapy with an (18)F labeled RGD-based probe in SKOV-3 xenograft-bearing mice. Tumour Biol 2014; 36:3285-91. [PMID: 25501513 DOI: 10.1007/s13277-014-2958-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/05/2014] [Indexed: 11/30/2022] Open
Abstract
So far, there is no satisfactory imaging modality to monitor antiangiogenesis therapy of ovarian cancer noninvasively. The aim of this study was to evaluate the effectiveness and sensibility of an (18)F labeled Arg-Gly-Asp (RGD) peptide in imaging and monitoring antiangiogenic responds in SKOV-3 xenograft-bearing mice. (18)F-FB-NH-PEG4-E[PEG4-c(RGDfK)]2 (denoted as (18)F-RGD2) was synthesized and employed in this study. Mice bearing ovarian cancer SKOV-3 tumors were used for biodistribution and microPET imaging studies compared with (18)F-FDG imaging. Animals were treated with low-dose paclitaxel and the effect of paclitaxel therapy on (18)F-RGD2 accumulation was investigated. Microvascular density (MVD) of SKOV-3 tumors was detected to assess the reliability of (18)F-RGD2 in antiangiogenesis monitoring. Biodistribution studies for (18)F-RGD2 revealed favorable in vivo pharmacokinetic properties, with significant levels of receptor-specific tumor uptake determined via blocking studies. MicroPET imaging results demonstrated high contrast visualization of SKOV-3 tumors. And tumor to background ratio (T/NT) of (18)F-RGD2 uptake was significantly higher than that of (18)F-FDG. Studies on antiangiogenic therapy demonstrated percentage of injected dose per gram of tissue (%ID/g) tumor uptake of (18)F-RGD2 which was obviously decreased in the treatment group than the control group, especially at 60 min (by 31.31 ± 7.18 %, P = 0.009) and 120 min (by 38.92 ± 8.31 %, P < 0.001) after injection of (18)F-RGD2. MVD measurement of SKOV-3 tumors confirmed the finding of the biodistribution studies in monitoring antiangiogenesis therapy. (18)F-RGD2, with favorable biodistribution properties and specific affinity, is a promising tracer for tumor imaging and monitoring antiangiogenesis therapy in ovarian cancer SKOV-3 xenograft-bearing mice.
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Affiliation(s)
- Guangjie Yang
- Department of Nuclear Medicine, Qilu Hospital, Shandong University, No.107 Wenhuaxi Road, Jinan, Shandong, China
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Yang G, Sun H, Kong Y, Hou G, Han J. Diversity of RGD radiotracers in monitoring antiangiogenesis of flavopiridol and paclitaxel in ovarian cancer xenograft-bearing mice. Nucl Med Biol 2014; 41:856-62. [DOI: 10.1016/j.nucmedbio.2014.08.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 01/28/2023]
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Shawky H, Tawfik H, Hewidy M. Weekly dose-dense paclitaxel and carboplatin in recurrent ovarian carcinoma: A phase II trial. J Egypt Natl Canc Inst 2014; 26:139-45. [DOI: 10.1016/j.jnci.2014.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 05/04/2014] [Accepted: 05/10/2014] [Indexed: 11/30/2022] Open
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Lorthois S, Lauwers F, Cassot F. Tortuosity and other vessel attributes for arterioles and venules of the human cerebral cortex. Microvasc Res 2014; 91:99-109. [DOI: 10.1016/j.mvr.2013.11.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 11/13/2013] [Accepted: 11/18/2013] [Indexed: 01/02/2023]
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Kumar S, Guru SK, Pathania AS, Kumar A, Bhushan S, Malik F. Autophagy triggered by magnolol derivative negatively regulates angiogenesis. Cell Death Dis 2013; 4:e889. [PMID: 24176847 PMCID: PMC3920944 DOI: 10.1038/cddis.2013.399] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 07/06/2013] [Accepted: 08/20/2013] [Indexed: 12/19/2022]
Abstract
Angiogenesis has a key role in the tumor progression and metastasis; targeting endothelial cell proliferation has emerged as a promising therapeutic strategy for the prevention of cancer. Previous studies have revealed a complex association between the process of angiogenesis and autophagy and its outcome on tumorigenesis. Autophagy, also known as type-II cell death, has been identified as an alternative way of cell killing in apoptotic-resistant cancer cells. However, its involvement in chemoresistance and tumor promotion is also well known. In this study, we used a derivate of natural product magnolol (Ery5), a potent autophagy inducer, to study the association between the autophagy and angiogenesis in both in vitro and in vivo model system. We found that the robust autophagy triggered by Ery5, inhibited angiogenesis and caused cell death independent of the apoptosis in human umbilical cord vein endothelial cells and PC-3 cells. Ery5 induced autophagy effectively inhibited cell proliferation, migration, invasion and tube formation. We further demonstrated that Ery5-mediated autophagy and subsequent inhibition of angiogenesis was reversed when autophagy was inhibited through 3-methyl adenine and knocking down of key autophagy proteins ATG7 and microtubule-associated protein light chain 3. While evaluating the negative regulation of autophagy on angiogenesis, it was interesting to find that angiogenic environment produced by the treatment of VEGF and CoCl2 remarkably downregulated the autophagy and autophagic cell death induced by Ery5. These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer.
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Affiliation(s)
- S Kumar
- 1] Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road Jammu, Jammu and Kashmir 180001, India [2] Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India
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Hallett MA, Dalal P, Sweatman TW, Pourmotabbed T. The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice. Nucleic Acid Ther 2013; 23:379-88. [PMID: 24083396 DOI: 10.1089/nat.2012.0348] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Catalytic oligonucleotides, known as DNAzymes, are a new class of nucleic acid-based gene therapy that have recently been used in preclinical animal studies to treat various cancers. In this study the systemic distribution, pharmacokinetics, and safety of intravenously administered anti-MMP (matrix metalloproteinase)-9 DNAzyme (AM9D) were determined in healthy FVB and in MMTV-polyoma virus middle T (PyMT) transgenic mice bearing mammary tumors. MMP-9 is known to be involved in tumor cell development, angiogenesis, invasion, and metastasis. Sulfur-35 ((35)S) labeled ([(35)S]-AM9D) administered intravenously, without the use of carrier molecules, to healthy and mammary tumor bearing MMTV-PyMT transgenic mice distributed to all major organs. The order of percentages of [(35)S]-AM9D accumulation in different organs of healthy and MMTV-PyMT mice were blood>liver>kidney>lung>spleen>heart and mammary tumor>blood≈liver>kidney>spleen>lung>heart, respectively. The amount of AM9D accumulated in mammary tumors 2 hours post injection was 0.6% and 0.2% higher than in either blood or liver, respectively, and its rate of initial clearance from mammary tissue was at least 50% slower than the other organs. Approximately 43% of the delivered dosage of [(35)S]-AM9D was cleared from the system via feces and urine over a period of 72 hours. No evidence of acute or chronic cytotoxicity, local or widespread, associated with AM9D treatment (up to 75 mg AM9D /kg of body weight) was observed in the organs examined. These data suggest that DNAzyme in general and AM9D in particular can be used systemically as a therapeutic agent to treat patients with breast cancer or other metastatic and surgically inaccessible tumors.
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Affiliation(s)
- Miranda A Hallett
- 1 Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center , Memphis Tennessee
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Pepe D, McCall M, Zheng H, Lopes LB. Protein transduction domain-containing microemulsions as cutaneous delivery systems for an anticancer agent. J Pharm Sci 2013; 102:1476-87. [PMID: 23436680 DOI: 10.1002/jps.23482] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 01/28/2013] [Accepted: 01/31/2013] [Indexed: 11/07/2022]
Abstract
In this study, we developed cationic microemulsions containing a protein transduction domain (penetratin) for optimizing paclitaxel localization within the skin. Microemulsions were prepared by mixing a surfactant blend (BRIJ:ethanol:propylene glycol 2:1:1, w/w/w) with monocaprylin (oil phase) at 1.3:1 ratio, and adding water at 30% (ME-30), 43% (ME-43), and 50% (ME-50). Electrical conductivity and viscosity measurements indicated that ME-30 is most likely a bicontinuous system, whereas ME-43 and ME-50 are water continuous. Their irritation potential, studied in bioengineered skin equivalents, decreased as aqueous content increased. Because ME-50 was not stable in the presence of paclitaxel (0.5%), ME-43 was selected for penetratin incorporation (0.4%). The microemulsion containing penetratin (ME-P) displayed zeta potential of +5.2 mV, and promoted a 1.8-fold increase in paclitaxel cutaneous (but not transdermal) delivery compared with the plain ME-43, whereas the enhancement promoted by another cationic microemulsion containing phytosphingosine was 1.3-fold. Compared with myvacet oil, ME-P promoted a larger increase on transepidermal water loss (twofold) than the plain or the phytosphingosine-containing microemulsions (1.5-fold), suggesting that penetratin addition increases the barrier-disrupting and penetration-enhancing effects of microemulsions. The ratio Δcutaneous/Δtransdermal delivery promoted by ME-P was the highest among the formulations, suggesting its potential for drug localization within cutaneous tumor lesions.
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Affiliation(s)
- Dominique Pepe
- Albany College of Pharmacy and Health Sciences, Albany, New York 12208, USA
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Martín M, Prat A, Rodríguez-Lescure A, Caballero R, Ebbert MTW, Munárriz B, Ruiz-Borrego M, Bastien RRL, Crespo C, Davis C, Rodríguez CA, López-Vega JM, Furió V, García AM, Casas M, Ellis MJ, Berry DA, Pitcher BN, Harris L, Ruiz A, Winer E, Hudis C, Stijleman IJ, Tuck DP, Carrasco E, Perou CM, Bernard PS. PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer. Breast Cancer Res Treat 2013; 138:457-66. [PMID: 23423445 PMCID: PMC3608881 DOI: 10.1007/s10549-013-2416-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 01/11/2013] [Indexed: 12/20/2022]
Abstract
To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical–pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.
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Affiliation(s)
- Miguel Martín
- Department of Medical Oncology, Instituto de Investigación Sanitaria Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.
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The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis 2013; 16:481-92. [PMID: 23389639 PMCID: PMC3682088 DOI: 10.1007/s10456-013-9334-0] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 01/15/2013] [Indexed: 11/03/2022]
Abstract
In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In the last decade, a number of studies showed that paclitaxel has antiangiogenic activity that could be ascribed to the inhibition of either tubule formation or cell migration, and to an antiproliferative effect towards activated endothelial cells. Furthermore, paclitaxel was shown to downregulate VEGF and Ang-1 expression in tumor cells, and to increase the secretion of TSP-1 in the tumor microenvironment. Moreover, the new pharmaceutical formulations of paclitaxel (such as liposome-encapsulated paclitaxel, ABI-007, and paclitaxel entrapped in emulsifying wax nanoparticles) enhanced the in vivo antiangiogenic activity of the drug. Thus, the preclinical data of paclitaxel may be exploited to implement a novel and rational therapeutic strategy to control tumor progression in patients.
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Kratz F, Warnecke A. Finding the optimal balance: Challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release 2012; 164:221-35. [DOI: 10.1016/j.jconrel.2012.05.045] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 05/08/2012] [Accepted: 05/26/2012] [Indexed: 10/28/2022]
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Rohrer Bley C, Furmanova P, Orlowski K, Grosse N, Broggini-Tenzer A, McSheehy PMJ, Pruschy M. Microtubule stabilising agents and ionising radiation: multiple exploitable mechanisms for combined treatment. Eur J Cancer 2012; 49:245-53. [PMID: 22683167 DOI: 10.1016/j.ejca.2012.05.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 05/07/2012] [Accepted: 05/08/2012] [Indexed: 12/18/2022]
Abstract
Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often driven by pragmatic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilising agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionising radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maximally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of molecular targeting agents, microtubule stabilising agents interfere with multiple cellular processes, which can be exploited as part of combined treatment modalities. Recent preclinical investigations on the combination of ionising radiation and microtubule stabilising agents reveal new mechanistic interactions on the cellular and tumour level and elucidate the supra-additive tumour response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitisation due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we summarise and allocate additive and synergistic effects induced by the combined treatment of clinically relevant microtubule stabilising agents and ionising radiation along a described radiobiological framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionising radiation.
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Affiliation(s)
- Carla Rohrer Bley
- Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
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Pinato DJ, Graham J, Gabra H, Sharma R. Evolving concepts in the management of drug resistant ovarian cancer: dose dense chemotherapy and the reversal of clinical platinum resistance. Cancer Treat Rev 2012; 39:153-60. [PMID: 22595680 DOI: 10.1016/j.ctrv.2012.04.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Revised: 04/13/2012] [Accepted: 04/17/2012] [Indexed: 11/17/2022]
Abstract
Despite the initially high response rate to standard front-line debulking surgery followed by platinum-based chemotherapy, the relapse rate in ovarian cancer is high and many patients will recur within 6 months of completing platinum based treatment. These patients may still require further chemotherapy despite being considered "platinum resistant". In this setting, response rates to conventionally scheduled second line platinum and non-platinum agents is low, ranging between 5% and 15%. There is an emerging body of evidence that in this scenario, chemotherapeutic activity can be enhanced using unconventionally scheduled "dose-dense" platinum and non-platinum based regimens with improved response rates of up to 65%. Randomised studies to evaluate the impact of this approach on survival in recurrent, platinum resistant disease are urgently required to confirm the promising phase II findings if there is to be a change in the standard of care of patients with platinum resistant disease. In this review we discuss the evolving strategies to overcome resistance in patients with platinum resistant ovarian cancer with a particular focus on alterations in dose schedule as a means of reversing platinum resistance.
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Affiliation(s)
- David J Pinato
- Division of Experimental Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0HS London, UK
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Peng JM, Chen YH, Hung SW, Chiu CF, Ho MY, Lee YJ, Lai TC, Hsiao M, Liang CM, Liang SM. Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting α5β1 integrin to down-regulate Akt and MMP-2. Br J Pharmacol 2012; 165:479-93. [PMID: 21740408 DOI: 10.1111/j.1476-5381.2011.01581.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND PURPOSE As prognosis for patients with metastatic ovarian cancer is generally poor, advances in treatment are needed. Here, we studied the mechanism of action of a recombinant viral capsid protein (rVP1) and explored its effect against ovarian tumour growth and metastasis in vivo. EXPERIMENTAL APPROACH The human ovarian cancer cell line SKOV3 and BALB/cAnN-Foxn1 female nude mice were used. Effects of rVP1 on the viability, invasive ability, matrix metalloproteinase (MMP)-2 activity and cancer cell proliferation and metastasis were determined by cell proliferation assay, Matrigel invasion assay, gelatin zymographic analysis, as well as bioluminescence imaging and immunohistological analysis in xenograft mouse models respectively. Levels of total and phosphorylated focal adhesion kinase (FAK), PKB/Akt, phosphatase and tensin homologue (PTEN) and glycogen synthase kinase-3β (GSK-3β) were detected by Western blotting. KEY RESULTS rVP1 promoted apoptosis and decreased invasion of human ovarian cancer cells. This effect of rVP1 was accompanied by activation of PTEN and GSK-3β as well as down-regulation of FAK, Akt and MMP-2. Anti-integrin antibodies or overexpression of constitutively active Akt reversed the cellular effects of rVP1. Orthotopic and intraperitoneal xenograft mouse models demonstrated that rVP1 attenuated survival and metastasis of human ovarian cancer SKOV3 cell line in vivo through selective regulation of Akt and GSK-3β activity as shown by bioluminescence imaging of mice and immunohistochemical analysis. CONCLUSION AND IMPLICATIONS These results indicate that negative regulation of Akt signalling and MMP-2 by rVP1 may have the potential to suppress ovarian tumour growth and metastasis in vivo.
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Affiliation(s)
- Jei-Ming Peng
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
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Wang Z, Chen J, Wang J, Ahn S, Li CM, Lu Y, Loveless VS, Dalton JT, Miller DD, Li W. Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis. Pharm Res 2012; 29:3040-52. [PMID: 22410804 DOI: 10.1007/s11095-012-0726-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 02/27/2012] [Indexed: 01/24/2023]
Abstract
PURPOSE To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. METHODS MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. RESULTS ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. CONCLUSIONS This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Animals
- Animals, Outbred Strains
- Antimitotic Agents/pharmacology
- Antineoplastic Agents/pharmacology
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Cycle/drug effects
- Cell Line, Tumor
- Colchicine/metabolism
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Female
- HEK293 Cells
- Humans
- Imidazoles/pharmacology
- Lung Neoplasms/metabolism
- Lung Neoplasms/prevention & control
- Lung Neoplasms/secondary
- Melanoma/drug therapy
- Melanoma/metabolism
- Melanoma/pathology
- Melanoma/secondary
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/pathology
- Mice
- Mice, Hairless
- Mice, Inbred C57BL
- Mice, SCID
- Microtubules/drug effects
- Microtubules/metabolism
- Neoplasm Metastasis
- Tubulin/metabolism
- Tubulin Modulators/pharmacology
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Affiliation(s)
- Zhao Wang
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave., Memphis, Tennessee 38163, USA
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[A case of primary pleural angiosarcoma metastasing to the bladder]. Nihon Hinyokika Gakkai Zasshi 2011; 102:686-90. [PMID: 22191277 DOI: 10.5980/jpnjurol.102.686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The patient was a 79-year-old man who underwent right extrapleural lucite ball plombage for pulmonary tuberculosis at aged 19. He was followed BPH with medication from May 2008 at our hospital. He presented with macrohematuria in January 2010, but cystoscopy and CT scan showed no significant abnormalities. He was admitted to complaining of general fatigue and anemia in February 2010. TURBT was performed 10 days after admission, and showed the bleeding sites with oozing in mucosa at the bilateral and posterior wall of the bladder. Neither CT nor cytological examinations were helpful in diagnosing this disease, although histological observation implied a possibility of malignant vasoformative tumor. He died one month after admission. Autopsy revealed a huge bloody mass at the right upper thoracic wall and same metastatic tumors of both adrenals, the bone, the stomach and the urinary bladder. Microscopic examination revealed that atypical cells had proliferated and formed vascular structures, which were stained positively with CD31, and vimentin. Finally, the diagnosis was made of pleural angiosarcoma and multiple metastasis. Metastatic angiosarcoma of the bladder is very rare and difficult to make definite diagnosis, however we have to keep in mind the presence of this disease.
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Dalton HJ, Yu X, Hu L, Kapp DS, Benjamin I, Monk BJ, Chan JK. An economic analysis of dose dense weekly paclitaxel plus carboplatin versus every-3-week paclitaxel plus carboplatin in the treatment of advanced ovarian cancer. Gynecol Oncol 2011; 124:199-204. [PMID: 22055763 DOI: 10.1016/j.ygyno.2011.09.028] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 09/14/2011] [Accepted: 09/19/2011] [Indexed: 10/15/2022]
Abstract
OBJECTIVE Compared with every-3-week paclitaxel (q3T) plus carboplatin, dose-dense weekly paclitaxel (ddT) plus carboplatin improved the survival of ovarian cancer patients. We performed a cost analysis comparing these two regimens. METHODS Using a Markov decision model, an acceptable incremental cost-effectiveness ratio (ICER) per progression-free life-year saved (PFLYS) was estimated. Cost of drugs, growth colony-stimulating factors, and transfusions were derived from Medicare reimbursement data. Survival and rates of complications were estimated based on the clinical trial. RESULTS Using a body weight and surface area of an average woman age 63, the estimated cost per cycle of ddT was $107 vs. $80 for q3T. The costs per cycle of combination chemotherapy including treatment administration were $873 for ddT and $535 for q3T. With a median progression-free survival (PFS) of 28 months with ddT vs. 17.2 months with q3T, the ICER was $5809 per PFLYS for ddT compared with q3T arm. Using a maximum ICER of $100,000 per LYS as cost-effective threshold, the ddT regimen was cost-effective. The ICER was most sensitive to the hazard rate for difference in PFS between the two regimens. A 4-month difference in PFS resulted in a $1200 change of ICER per PFLYS. The ICER was also sensitive to overall survival difference, rate of hematological toxicity, and rate of discontinuation. CONCLUSIONS In this economic model, dose-dense weekly paclitaxel is a cost-effective treatment option for advanced ovarian cancer.
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Affiliation(s)
- Heather J Dalton
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
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Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 2011; 12:1109-17. [PMID: 21992853 DOI: 10.1016/s1470-2045(11)70244-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. METHODS For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. FINDINGS From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). INTERPRETATION Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. FUNDING US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
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A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 122:111-5. [PMID: 21497382 DOI: 10.1016/j.ygyno.2011.03.036] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 03/25/2011] [Accepted: 03/30/2011] [Indexed: 11/22/2022]
Abstract
BACKGROUND Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel. METHODS Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n = 5) or recurrence within 6 months of treatment completion (n = 42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m² days 1, 8, and 15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%). RESULTS Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34-78) years, serous histology: 72%, and high-grade: 81%. EFFICACY one complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95% CI: 2.2-6.7); overall survival was 17.4 months (95% CI: 13.2-20.8). Seventeen patients (36%) had PFS > 6 months. TOXICITY there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1. CONCLUSIONS Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.
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Bayless KJ, Johnson GA. Role of the cytoskeleton in formation and maintenance of angiogenic sprouts. J Vasc Res 2011; 48:369-85. [PMID: 21464572 DOI: 10.1159/000324751] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Accepted: 01/10/2011] [Indexed: 12/19/2022] Open
Abstract
Angiogenesis is the formation of new blood vessels from pre-existing structures, and is a key step in tissue and organ development, wound healing and pathological events. Changes in cell shape orchestrated by the cytoskeleton are integral to accomplishing the various steps of angiogenesis, and an intact cytoskeleton is also critical for maintaining newly formed structures. This review focuses on how the 3 main cytoskeletal elements--microfilaments, microtubules, and intermediate filaments--regulate the formation and maintenance of angiogenic sprouts. Multiple classes of compounds target microtubules and microfilaments, revealing much about the role of actin and tubulin and their associated molecules in angiogenic sprout formation and maintenance. In contrast, intermediate filaments are much less studied, yet intriguing evidence suggests a vital, but unresolved, role in angiogenic sprouting. This review discusses evidence for regulatory molecules and pharmacological compounds that affect actin, microtubule and intermediate filament dynamics to alter various steps of angiogenesis, including endothelial sprout formation and maintenance.
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Affiliation(s)
- Kayla J Bayless
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
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