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Smith ER, Huang M, Schlumbrecht MP, George SH, Xu XX. Rationale for combination of paclitaxel and CDK4/6 inhibitor in ovarian cancer therapy - non-mitotic mechanisms of paclitaxel. Front Oncol 2022; 12:907520. [PMID: 36185294 PMCID: PMC9520484 DOI: 10.3389/fonc.2022.907520] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
Taxanes and CDK4/6 inhibitors (CDK4/6i) are two families of successful anti-mitotic drugs used in the treatment of solid tumors. Paclitaxel, representing taxane compounds, has been used either alone or in combination with other agents (commonly carboplatin/cisplatin) in the treatment of many solid tumors including ovarian, breast, lung, prostate cancers, and Kaposi's sarcoma. Paclitaxel has been routinely prescribed in cancer treatment since the 1990s, and its prominent role is unlikely to be replaced in the foreseeable future. Paclitaxel and other taxanes work by binding to and stabilizing microtubules, causing mitotic arrest, aberrant mitosis, and cell death. CDK4/6i (palbociclib, ribociclib, abemaciclib) are relatively new cell cycle inhibitors that have been found to be effective in breast cancer treatment, and are currently being developed in other solid tumors. CDK4/6i blocks cell cycle progression at the G1 phase, resulting in cell death by mechanisms not yet fully elucidated. At first glance, paclitaxel and CDK4/6i are unlikely synergistic agents as both are cell cycle inhibitors that work at different phases of the cell cycle, and few clinical trials have yet considered adding CDK4/6i to existing paclitaxel chemotherapy. However, recent findings suggest the importance of a non-mitotic mechanism of paclitaxel in cancer cell death and pre-clinical data support rationale for a strategic paclitaxel and CDK4/6i combination. In mouse tumor model studies, drug sequencing resulted in differential efficacy, indicating complex biological interactions of the two drugs. This article reviews the rationales of combining paclitaxel with CDK4/6i as a potential therapeutic option in recurrent ovarian cancer.
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Affiliation(s)
- Elizabeth R. Smith
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Marilyn Huang
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Matthew P. Schlumbrecht
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Sophia H.L. George
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Xiang-Xi Xu
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, United States
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Amaya C, Smith ER, Xu XX. Low Intensity Ultrasound as an Antidote to Taxane/Paclitaxel-induced Cytotoxicity. J Cancer 2022; 13:2362-2373. [PMID: 35517405 PMCID: PMC9066212 DOI: 10.7150/jca.71263] [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: 01/20/2022] [Accepted: 04/04/2022] [Indexed: 11/25/2022] Open
Abstract
The taxane family of compounds, including Taxol/paclitaxel and Taxotere/docetaxel, are surprisingly successful drugs used in combination or alone for the treatment of most major solid tumors, especially metastatic cancer. The drugs are commonly used in regimen with other agents (often platinum drugs) as frontline treatment, or used as a single agent in a dose dense regimen for recurrent cancer. The major side effects of taxanes are peripheral neuropathy, alopecia, and neutropenia, which are grave burden for patients and limit the full potential of the taxane drugs. Especially in the current treatment protocol for peripheral neuropathy, taxane dosage is reduced once the symptoms present, resulting in the loss of full or optimal cancer killing activity. Substantial efforts have been made to address the problem of cytotoxic side effects of taxanes, though strategies remain very limited. Following administration of the taxane compound by infusion, taxane binds to cellular microtubules and is sequestered within the cells for several days. Taxane stabilizes and interferes with microtubule function, leading to ultimate death of cancer cells, but also damages hair follicles, peripheral neurons, and hemopoietic stem cells. Currently, cryo-treatment is practiced to limit exposure and side effects of the drug during infusion, though the effectiveness is uncertain or limited. A recent laboratory finding may provide a new strategy to counter taxane cytotoxicity, that a brief exposure to low density ultrasound waves was sufficient to eliminate paclitaxel cytotoxicity cells in culture by transiently breaking microtubule filaments, which were then relocated to lysosomes for disposal. Thus, ultrasonic force to break rigid microtubules is an effective solution to counter taxane cytotoxicity. The discovery and concept of low intensity ultrasound as an antidote may have the potential to provide a practical strategy to counter paclitaxel-induced peripheral neuropathy and alopecia that resulted from chemotherapy. Taxanes are a class of important drugs used in chemotherapy to treat several major cancers. This article reviews a new laboratory discovery that ultrasound can be used as an antidote for the peripheral cytotoxicity of taxane drugs and discusses the potential development and application of low intensity ultrasound to prevent side effects in chemotherapeutic treatment of cancer patients.
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Affiliation(s)
- Celina Amaya
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Elizabeth R Smith
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Xiang-Xi Xu
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 1120 NW 14th Street, Miami, FL, USA
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Hyperthermia Treatment as a Promising Anti-Cancer Strategy: Therapeutic Targets, Perspective Mechanisms and Synergistic Combinations in Experimental Approaches. Antioxidants (Basel) 2022; 11:antiox11040625. [PMID: 35453310 PMCID: PMC9030926 DOI: 10.3390/antiox11040625] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 02/04/2023] Open
Abstract
Despite recent developments in diagnosis and treatment options, cancer remains one of the most critical threats to health. Several anti-cancer therapies have been identified, but further research is needed to provide more treatment options that are safe and effective for cancer. Hyperthermia (HT) is a promising treatment strategy for cancer because of its safety and cost-effectiveness. This review summarizes studies on the anti-cancer effects of HT and the detailed mechanisms. In addition, combination therapies with anti-cancer drugs or natural products that can effectively overcome the limitations of HT are reviewed because HT may trigger protective events, such as an increase of heat shock proteins (HSPs). In the 115 reports included, the mechanisms related to apoptosis, cell cycle, reactive oxygen species, mitochondrial membrane potential, DNA damage, transcription factors and HSPs were considered important. This review shows that HT is an effective inducer of apoptosis. Moreover, the limitations of HT may be overcome using combined therapy with anti-cancer drugs or natural products. Therefore, appropriate combinations of such agents with HT will exert maximal effects to treat cancer.
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Imashiro C, Takeshita H, Morikura T, Miyata S, Takemura K, Komotori J. Development of accurate temperature regulation culture system with metallic culture vessel demonstrates different thermal cytotoxicity in cancer and normal cells. Sci Rep 2021; 11:21466. [PMID: 34728686 PMCID: PMC8563756 DOI: 10.1038/s41598-021-00908-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022] Open
Abstract
Hyperthermia has been studied as a noninvasive cancer treatment. Cancer cells show stronger thermal cytotoxicity than normal cells, which is exploited in hyperthermia. However, the absence of methods evaluating the thermal cytotoxicity in cells prevents the development of hyperthermia. To investigate the thermal cytotoxicity, culture temperature should be regulated. We, thus, developed a culture system regulating culture temperature immediately and accurately by employing metallic culture vessels. Michigan Cancer Foundation-7 cells and normal human dermal fibroblasts were used for models of cancer and normal cells. The findings showed cancer cells showed stronger thermal cytotoxicity than normal cells, which is quantitatively different from previous reports. This difference might be due to regulated culture temperature. The thermal stimulus condition (43 °C/30 min) was, further, focused for assays. The mRNA expression involving apoptosis changed dramatically in cancer cells, indicating the strong apoptotic trend. In contrast, the mRNA expression of heat shock protein (HSP) of normal cells upon the thermal stimulus was stronger than cancer cells. Furthermore, exclusively in normal cells, HSP localization to nucleus was confirmed. These movement of HSP confer thermotolerance to cells, which is consistent with the different thermal cytotoxicity between cancer and normal cells. In summary, our developed system can be used to develop hyperthermia treatment.
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Affiliation(s)
- Chikahiro Imashiro
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan.
| | - Haruka Takeshita
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan
| | - Takashi Morikura
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan
| | - Shogo Miyata
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan
| | - Kenjiro Takemura
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan
| | - Jun Komotori
- Department of Mechanical Engineering, Keio University, Yokohama, 223-8522, Japan.
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Amaya C, Luo S, Baigorri J, Baucells R, Smith ER, Xu XX. Exposure to low intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells. BMC Cancer 2021; 21:981. [PMID: 34470602 PMCID: PMC8408969 DOI: 10.1186/s12885-021-08722-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 08/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Paclitaxel (Taxol) is a microtubule-stabilizing drug used to treat several solid tumors, including ovarian, breast, non-small cell lung, and pancreatic cancers. The current treatment of ovarian cancer is chemotherapy using paclitaxel in combination with carboplatin as a frontline agent, and paclitaxel is also used in salvage treatment as a second line drug with a dose intensive regimen following recurrence. More recently, a dose dense approach for paclitaxel has been used to treat metastatic breast cancer with success. Paclitaxel binds to beta tubulin with high affinity and stabilizes microtubule bundles. As a consequence of targeting microtubules, paclitaxel kills cancer cells through inhibition of mitosis, causing mitotic catastrophes, and by additional, not yet well defined non-mitotic mechanism(s). RESULTS In exploring methods to modulate activity of paclitaxel in causing cancer cell death, we unexpectedly found that a brief exposure of paclitaxel-treated cells in culture to low intensity ultrasound waves prevented the paclitaxel-induced cytotoxicity and death of the cancer cells. The treatment with ultrasound shock waves was found to transiently disrupt the microtubule cytoskeleton and to eliminate paclitaxel-induced rigid microtubule bundles. When cellular microtubules were labelled with a fluorescent paclitaxel analog, exposure to ultrasound waves led to the disassembly of the labeled microtubules and localization of the signals to perinuclear compartments, which were determined to be lysosomes. CONCLUSIONS We suggest that ultrasound disrupts the paclitaxel-induced rigid microtubule cytoskeleton, generating paclitaxel bound fragments that undergo degradation. A new microtubule network forms from tubulins that are not bound by paclitaxel. Hence, ultrasound shock waves are able to abolish paclitaxel impact on microtubules. Thus, our results demonstrate that a brief exposure to low intensity ultrasound can reduce and/or eliminate cytotoxicity associated with paclitaxel treatment of cancer cells in cultures.
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Affiliation(s)
- Celina Amaya
- Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877], 1550 NW 10th Avenue, Miami, FL, 33136, USA
| | - Shihua Luo
- Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877], 1550 NW 10th Avenue, Miami, FL, 33136, USA
| | - Julio Baigorri
- HHMI High School Scholars Program, Department of Undergraduate Research and Community Outreach, University of Miami, Miami, FL, 33146, USA
| | - Rogelio Baucells
- HHMI High School Scholars Program, Department of Undergraduate Research and Community Outreach, University of Miami, Miami, FL, 33146, USA
| | - Elizabeth R Smith
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Xiang-Xi Xu
- Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877], 1550 NW 10th Avenue, Miami, FL, 33136, USA.
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Park S, Park SJ, Lee HS, Ham J, Lee EJ, Kim J, Ryu S, Seol A, Lim W, Lee JC, Song G, Kim HS. Establishment of an Experimental System for Intraperitoneal Chemotherapy in a Rat Model. In Vivo 2021; 35:2703-2710. [PMID: 34410959 DOI: 10.21873/invivo.12554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/10/2021] [Accepted: 07/15/2021] [Indexed: 01/28/2023]
Abstract
AIM To establish an experimental system for comparing different methods of intraperitoneal chemotherapy in a rat model. MATERIALS AND METHODS We used six-week-old Sprague-Dawley rats, and created an early postoperative intraperitoneal chemotherapy (EPIC) system using 18-gauge syringes and evacuators, and a hyperthermic intraperitoneal chemotherapy (HIPEC) system using two peristaltic pumps which controlled the flow rate and temperature. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was achieved using a nozzle for dispersing aerosols at a flow rate up to 41.5 ml/min. The distribution and intensity of 0.2% trypan blue dye was compared among three methods. RESULTS The distribution was limited and the intensity was weak after EPIC, and the dye stained moderately in gravity-dependent regions after HIPEC. On the other hand, the distribution was the most comprehensive, and the intensity was the greatest after PIPAC. CONCLUSION This experimental system in a rat model may reflect the comparative effect among EPIC, HIPEC and PIPAC in humans.
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Affiliation(s)
- Sunwoo Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Soo Jin Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Su Lee
- Interdisciplinary Program in Bioengineering, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Jiyeon Ham
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Eun Ji Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Junsik Kim
- Interdisciplinary Program in Bioengineering, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Soomin Ryu
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Aeran Seol
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Whasun Lim
- Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea
| | - Jung Chan Lee
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Gwonhwa Song
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea;
| | - Hee Seung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea;
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Farkaš B, de Leeuw NH. A Perspective on Modelling Metallic Magnetic Nanoparticles in Biomedicine: From Monometals to Nanoalloys and Ligand-Protected Particles. MATERIALS (BASEL, SWITZERLAND) 2021; 14:3611. [PMID: 34203371 PMCID: PMC8269646 DOI: 10.3390/ma14133611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022]
Abstract
The focus of this review is on the physical and magnetic properties that are related to the efficiency of monometallic magnetic nanoparticles used in biomedical applications, such as magnetic resonance imaging (MRI) or magnetic nanoparticle hyperthermia, and how to model these by theoretical methods, where the discussion is based on the example of cobalt nanoparticles. Different simulation systems (cluster, extended slab, and nanoparticle models) are critically appraised for their efficacy in the determination of reactivity, magnetic behaviour, and ligand-induced modifications of relevant properties. Simulations of the effects of nanoscale alloying with other metallic phases are also briefly reviewed.
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Affiliation(s)
- Barbara Farkaš
- School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK;
| | - Nora H. de Leeuw
- School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK;
- School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
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Parray A, Gupta V, Chaudhari VA, Shrikhande SV, Bhandare MS. Role of intraperitoneal chemotherapy in gastric cancer. SURGERY IN PRACTICE AND SCIENCE 2021. [DOI: 10.1016/j.sipas.2020.100025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Smith ER, Xu XX. Breaking malignant nuclei as a non-mitotic mechanism of taxol/paclitaxel. JOURNAL OF CANCER BIOLOGY 2021; 2:86-93. [PMID: 35048083 PMCID: PMC8765745 DOI: 10.46439/cancerbiology.2.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Discovered in a large-scale screening of natural plant chemicals, Taxol/paclitaxel and the taxane family of compounds are surprisingly successful anti-cancer drugs, used in treatment of the majority of solid tumors, and especially suitable for metastatic and recurrent cancer. Paclitaxel is often used in combination with platinum agents and is administrated in a dose dense regimen to treat recurrent cancer. The enthusiasm and clinical development were prompted by the discovery that Taxol binds beta-tubulins specifically found within microtubules and stabilizes the filaments, and consequently inhibits mitosis. However, questions on how paclitaxel suppresses cancer persist, as other specific mitotic inhibitors are impressive in pre-clinical studies but fail to achieve significant clinical activity. Thus, additional mechanisms, such as promoting mitotic catastrophe and impacting non-mitotic targets, have been proposed and studied. A good understanding of how paclitaxel, and additional new microtubule stabilizing agents, kill cancer cells will advance the clinical application of these common chemotherapeutic agents. A recent study provides a potential non-mitotic mechanism of paclitaxel action, that paclitaxel-induced rigid microtubules act to break malleable cancer nuclei into multiple micronuclei. Previous studies have established that cancer cells have a less sturdy, more pliable nuclear envelope due to the loss or reduction of lamin A/C proteins. Such changes in nuclear structure provide a selectivity for paclitaxel to break the nuclear membrane and kill cancer cells over non-neoplastic cells that have a sturdier nuclear envelope. The formation of multiple micronuclei appears to be an important aspect of paclitaxel in the killing of cancer cells, either by a mitotic or non-mitotic mechanism. Additionally, by binding to microtubule, paclitaxel is readily sequestered and concentrated within cells. This unique pharmacokinetic property allows the impact of paclitaxel on cells to persist for several days, even though the circulating drug level is much reduced following drug administration/infusion. The retention of paclitaxel within cells likely is another factor contributing to the efficacy of the drugs. Overall, the new understanding of Taxol/paclitaxel killing mechanism-rigid microtubule-induced multiple micronucleation-will likely provide new strategies to overcome drug resistance and for rational drug combination.
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Affiliation(s)
- Elizabeth R. Smith
- Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Xiang-Xi Xu
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, United States
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, United States
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Kong XX, Jiang S, Liu T, Liu GF, Dong M. Paclitaxel increases sensitivity of SKOV3 cells to hyperthermia by inhibiting heat shock protein 27. Biomed Pharmacother 2020; 132:110907. [PMID: 33113434 DOI: 10.1016/j.biopha.2020.110907] [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: 03/26/2020] [Revised: 09/21/2020] [Accepted: 10/17/2020] [Indexed: 01/04/2023] Open
Abstract
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment strategy for patients with peritoneal metastasis of ovarian cancer. Heat shock proteins (HSPs) play an important role in cellular stress during HIPEC treatment. The aim of the present study was to investigate whether paclitaxel can exert antitumor effects by inhibiting heat shock protein 27 (HSP27) expression during HIPEC treatment. Cell viability was detected by CCK8 assay. We used Western blot analysis to detect HSP27 expression under hyperthermia conditions with or without paclitaxel in SKOV3 cells. To further examine the role of HSP27 in the apoptosis, Bcl-2, Bax and Caspase-3 protein expression were additionally determined after reducing HSP27 levels using an siRNA strategy, and apoptosis was detected using the Annexin V/PI assay. The upregulation of HSP27 expression was accompanied with a rise in temperature. In addition, HSP27 could promote Bcl-2 expression, inhibit Bax and Caspase-3 expression, reduce the Bax / Bcl-2 ratio markedly in SKOV3 cells. Furthermore, paclitaxel could upregulate the Bax / Bcl-2 ratio by inhibiting HSP27 expression, and in turn, promoting apoptosis due to hyperthermia. Paclitaxel could also promote apoptosis by inhibiting HSP27 in SKOV3 cells. Our results demonstrate a synergistic effect between paclitaxel and hyperthermia at the cellular level.
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Affiliation(s)
- Xiang-Xue Kong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Shuai Jiang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Tong Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Gao-Feng Liu
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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de Bree E, Michelakis D. An overview and update of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Expert Opin Pharmacother 2020; 21:1479-1492. [PMID: 32486865 DOI: 10.1080/14656566.2020.1766024] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Despite, the strong rationale and evidence of the benefit of postoperative intraperitoneal chemotherapy in advanced ovarian cancer, it has not been widely adopted, mainly due to its high morbidity and logistical difficulties. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a more tolerable and technically feasible method of intraperitoneal chemotherapy, whereas other potential advantages include homogenous drug distribution, application before tumor regrowth and combination with hyperthermia, which is directly cytotoxic and enhances the efficacy of many drugs. AREAS COVERED In this review, the authors explain the rationale and indications for cytoreductive surgery (CRS) and HIPEC in advanced ovarian cancer. Data of major clinical studies, meta-analyses, and recent randomized trials are discussed. EXPERT OPINION After many encouraging clinical studies and meta-analyses, a recent randomized study demonstrated survival benefit for HIPEC during interval CRS in primary ovarian cancer, without increased morbidity, whereas another implied its benefit in recurrent ovarian cancer. Results of recently completed and numerous ongoing randomized studies will further determine the benefit of HIPEC in ovarian cancer at different time points. Patient selection and appraisal of the best protocols are crucial. The field of gynecological oncology will most likely evolve to include HIPEC eventually as a routine treatment for ovarian cancer.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital , Heraklion, Greece
| | - Dimosthenis Michelakis
- Department of Surgical Oncology, Medical School of Crete University Hospital , Heraklion, Greece
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Liao S, Hu X, Liu Z, Lin Y, Liang R, Zhang Y, Li Q, Li Y, Liao X. Synergistic action of microwave-induced mild hyperthermia and paclitaxel in inducing apoptosis in the human breast cancer cell line MCF-7. Oncol Lett 2019; 17:603-615. [PMID: 30655807 PMCID: PMC6313200 DOI: 10.3892/ol.2018.9629] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 10/15/2018] [Indexed: 11/05/2022] Open
Abstract
Microwave mild hyperthermia and paclitaxel have been reported to be involved in variety of solid tumors. However, rare related researches have been accomplished via directly killing tumor cells using thermochemotherapy. In order to clarify the potential synergy between microwave-induced hyperthermia at temperatures <41°C and paclitaxel chemotherapy for inhibiting the growth of the human breast cancer cell line MCF-7, an MTT assay was used. The MCF-7 cells cultured in vitro were treated with paclitaxel alone, treated with microwave-induced hyperthermia for 2 h alone (at 40, 40.5 or 41°C), or treated with a combination of paclitaxel and 2 h of hyperthermia (at 40, 40.5 or 41°C). Flow cytometry was used to determine the cell apoptosis rate and it was demonstrated that paclitaxel decreased cell viability in a dose-dependent manner. Alone, hyperthermia for 2 h at 41°C induced apoptosis in MCF-7 cells, to a greater extent compared with hyperthermia for 2 h at 40.0 or 40.5°C (P<0.05). Together, paclitaxel and 2 h of hyperthermia at 40.5°C induced significantly increased apoptosis compared with either treatment alone (P<0.05). Increasing the temperature to 41°C in combination with paclitaxel increased the apoptotic ratio from 12.21±1.02% to 16.36±2.39%. The apoptotic ratio correlated positively with hyperthermia temperature and duration following hyperthermia, as did the synergistic effect obtained by combining hyperthermia and paclitaxel. Notably, the combination of 5 µg/ml paclitaxel and 2 h of hyperthermia at 40°C enhanced MCF-7 cell proliferation. Mild hyperthermia may exert anti-tumor effects by inducing apoptosis, and combining hyperthermia with paclitaxel synergistically induces apoptosis. Paclitaxel dose and hyperthermia temperature require careful optimization, as low-dose paclitaxel combined with hyperthermia at an insufficient temperature may enhance breast cancer proliferation.
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Affiliation(s)
- Sina Liao
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaohua Hu
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhihui Liu
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yan Lin
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Rong Liang
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yumei Zhang
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Qian Li
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yongqiang Li
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaoli Liao
- Department of The First Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Cesna V, Sukovas A, Jasukaitiene A, Naginiene R, Barauskas G, Dambrauskas Z, Paskauskas S, Gulbinas A. Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells. World J Gastroenterol 2018; 24:1072-1083. [PMID: 29563752 PMCID: PMC5850127 DOI: 10.3748/wjg.v24.i10.1072] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/02/2018] [Accepted: 01/15/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells.
METHODS AGS (gastric cancer cell line), Caco-2 (colon cancer cell line) and T3M4 (pancreatic cancer cell line) were treated by cisplatin and different temperature setting (37 °C to 45 °C) either in isolation, or in combination. Treatment lasted for one hour. 48 h after the treatment viability was evaluated by MTT, cell apoptosis by Annexin V-PE and 7ADD flow cytometry. Intracellular cisplatin concentration was measured immediately after the treatment, using mass spectrometry. Isobologram analysis was performed to evaluate the mathematical combined effect of temperature and cisplatin.
RESULTS AGS cells were the most sensitive to isolated application of hyperthermia. Hyperthermia, in addition to cisplatin treatment, did not provoke a synergistic effect at intervals from 37 °C to 41 °C in neither cancer cell line. However, a temperature of 43 °C enhanced cisplatin cytotoxicity for Caco-2 cells. Moreover, isobologram analysis revealed mathematical antagonistic effects of cisplatin and temperature combined treatment in AGS cells; variations between synergistic, additive, and antagonistic effects in Caco-2 cells; and additive and antagonistic effects in T3M4 cells. Combined treatment enhanced initiation of cell apoptosis in AGS, Caco-2, and T3M4 cells by 61%, 20%, and 19% respectively. The increase of intracellular cisplatin concentration was observed at 43 °C by 30%, 20%, and 18% in AGS, Caco-2, and T3M4 cells, respectively.
CONCLUSION In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.
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Affiliation(s)
- Vaidotas Cesna
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Arturas Sukovas
- Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Aldona Jasukaitiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Rima Naginiene
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Giedrius Barauskas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Zilvinas Dambrauskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Saulius Paskauskas
- Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
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15
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Ji ZH, Peng KW, Li Y. Intraperitoneal free cancer cells in gastric cancer: pathology of peritoneal carcinomatosis and rationale for intraperitoneal chemotherapy/hyperthermic intraperitoneal chemotherapy in gastric cancer. Transl Gastroenterol Hepatol 2016; 1:69. [PMID: 28138635 DOI: 10.21037/tgh.2016.08.03] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 08/15/2016] [Indexed: 12/19/2022] Open
Abstract
Peritoneal carcinomatosis (PC) is one of the most common causes of death in gastric cancer patients. Intraperitoneal free cancer cells (IFCCs) play a very important role in forming PC, but the administration of intraperitoneal chemotherapy (IPC) and/or hyperthermic intraperitoneal chemotherapy (HIPEC) could be an effective treatment for IFCCs. This review focuses on the origin of IFCCs, the mechanism of PC formatting, the rationale of IPC/HIPEC, and the current clinical trials on IPC/HIPEC to treat advanced gastric cancer patients.
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Affiliation(s)
- Zhong-He Ji
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
| | - Kai-Wen Peng
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
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Badr El-Din NK, Ali DA, Alaa El-Dein M, Ghoneum M. Enhancing the Apoptotic Effect of a Low Dose of Paclitaxel on Tumor Cells in Mice by Arabinoxylan Rice Bran (MGN-3/Biobran). Nutr Cancer 2016; 68:1010-20. [PMID: 27367621 DOI: 10.1080/01635581.2016.1192204] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In this study, we examine the ability of arabinoxylan rice bran (MGN-3/Biobran) to enhance the apoptotic effect of paclitaxel (Taxol) at low concentration [2 mg/kg body weight (BW)] in animals bearing Ehrlich ascites carcinoma (EAC) cells and elucidate its mechanisms of action. On Day 8 following tumor cells inoculation, mice bearing tumors were administered MGN-3 alone (40 mg/kg BW), paclitaxel alone, or MGN-3 plus paclitaxel. On Day 30 post-tumor inoculation, we observed significant suppression of tumor volume (TV) with paclitaxel alone (59%), MGN-3 alone (77%), and MGN-3 plus paclitaxel (88%). Inhibition of tumor growth post-treatment with both agents, as compared with either treatment alone, was associated with a decrease in cell proliferation, a marked increase in the sub-G0/G1 population, an increase in DNA damage and apoptosis of tumor cells, and a significant maximization of the apoptosis index (AI)/proliferation index (PrI) ratio. Histopathological and electron microscopy examination of the combined treatment group showed an increase in the degenerative regions of the solid tumor tissue and abundant apoptotic cells. These data suggest that MGN-3 supplementation enhances tumor cell demise in the presence of a low dose of chemotherapeutic agent via apoptotic mechanism.
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Affiliation(s)
- Nariman K Badr El-Din
- a Department of Zoology , Faculty of Science, University of Mansoura , Mansoura , Egypt
| | - Doaa A Ali
- a Department of Zoology , Faculty of Science, University of Mansoura , Mansoura , Egypt
| | - Mai Alaa El-Dein
- a Department of Zoology , Faculty of Science, University of Mansoura , Mansoura , Egypt
| | - Mamdooh Ghoneum
- b Department of Otolaryngology , Charles Drew University of Medicine and Science , Los Angeles , California , USA
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17
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Christie C, Molina S, Gonzales J, Berg K, Nair RK, Huynh K, Madsen SJ, Hirschberg H. Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization. BIOMEDICAL OPTICS EXPRESS 2016; 7:1240-1250. [PMID: 27446650 PMCID: PMC4929636 DOI: 10.1364/boe.7.001240] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/04/2016] [Accepted: 02/10/2016] [Indexed: 06/06/2023]
Abstract
Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm(-2) using an irradiance of 5 mW cm(-2). Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C.
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Affiliation(s)
- Catherine Christie
- Beckman Laser Institute, University of California, Irvine,, Irvine, CA 92612 USA
| | - Stephanie Molina
- Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV 89154, USA
| | - Jonathan Gonzales
- Beckman Laser Institute, University of California, Irvine,, Irvine, CA 92612 USA
| | - Kristian Berg
- Dept. of Radiation Biology The Norwegian Radium Hospital, Oslo University Hospital, Oslo Norway
| | - Rohit Kumar Nair
- Beckman Laser Institute, University of California, Irvine,, Irvine, CA 92612 USA
| | - Khoi Huynh
- Beckman Laser Institute, University of California, Irvine,, Irvine, CA 92612 USA
| | - Steen J. Madsen
- Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV 89154, USA
| | - Henry Hirschberg
- Beckman Laser Institute, University of California, Irvine,, Irvine, CA 92612 USA
- Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV 89154, USA
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18
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Madsen SJ, Shih EC, Peng Q, Christie C, Krasieva T, Hirschberg H. Photothermal enhancement of chemotherapy mediated by gold-silica nanoshell-loaded macrophages: in vitro squamous cell carcinoma study. JOURNAL OF BIOMEDICAL OPTICS 2016; 21:18004. [PMID: 26811077 PMCID: PMC4881286 DOI: 10.1117/1.jbo.21.1.018004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 12/15/2015] [Indexed: 05/03/2023]
Abstract
Moderate hyperthermia (MHT) has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of commonly used chemotherapeutic agents with MHT induced by near-infrared (NIR) activation of gold nanoshell (AuNS)-loaded macrophages (Ma). AuNS-loaded murine Ma combined with human FaDu squamous cells, in hybrid monolayers, were subjected to three cytotoxic drugs (doxorubicin, bleomycin, cisplatin) with or without NIR laser irradiation. For all three drugs, efficacy was increased by NIR activation of AuNS-loaded Ma. The results of this in vitro study provide proof-of-concept for the use of AuNS-loaded Ma for photothermal enhancement of the effects of chemotherapy on squamous cell carcinoma.
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Affiliation(s)
- Steen J. Madsen
- University of Nevada, Department of Health Physics and Diagnostic Sciences, P.O. Box 453037, 4505 South Maryland Parkway, Las Vegas, Nevada 89154, United States
- Address all correspondence to: Steen J. Madsen, E-mail:
| | - En-Chung Shih
- University of Nevada, Department of Health Physics and Diagnostic Sciences, P.O. Box 453037, 4505 South Maryland Parkway, Las Vegas, Nevada 89154, United States
| | - Qian Peng
- Oslo University Hospital, Department of Pathology, Montebello, N-03 10, Oslo, Norway
| | - Catherine Christie
- University of California, Beckman Laser Institute, 1002 Health Sciences Road East, Irvine, California 92612, United States
| | - Tatiana Krasieva
- University of California, Beckman Laser Institute, 1002 Health Sciences Road East, Irvine, California 92612, United States
| | - Henry Hirschberg
- University of Nevada, Department of Health Physics and Diagnostic Sciences, P.O. Box 453037, 4505 South Maryland Parkway, Las Vegas, Nevada 89154, United States
- University of California, Beckman Laser Institute, 1002 Health Sciences Road East, Irvine, California 92612, United States
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Cascales-Campos P, Gil J, Feliciangeli E, Parrilla P. HIPEC in ovarian cancer: Treatment of a new era or is it the end of the pipeline? Gynecol Oncol 2015; 139:363-8. [DOI: 10.1016/j.ygyno.2015.06.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 05/15/2015] [Accepted: 06/08/2015] [Indexed: 01/21/2023]
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Braam HJ, Schellens JH, Boot H, van Sandick JW, Knibbe CA, Boerma D, van Ramshorst B. Selection of chemotherapy for hyperthermic intraperitoneal use in gastric cancer. Crit Rev Oncol Hematol 2015; 95:282-96. [PMID: 25921419 DOI: 10.1016/j.critrevonc.2015.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 01/22/2015] [Accepted: 04/07/2015] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Several studies have shown the potential benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients. At present the most effective chemotherapeutic regime in HIPEC for gastric cancer is unknown. The aim of this review was to provide a comprehensive overview of chemotherapeutic agents used for HIPEC in gastric cancer. METHODS A literature search was conducted using the PubMed database to identify studies on chemotherapy used for HIPEC in gastric cancer patients. RESULTS AND CONCLUSION The chemotherapeutic regime of choice in HIPEC for gastric cancer has yet to be determined. The wide variety in studies and study parameters, such as chemotherapeutic agents, dosage, patient characteristics, temperature of perfusate, duration of perfusion, carrier solutions, intraperitoneal pressure and open or closed perfusion techniques, warrant more experimental and clinical studies to determine the optimal treatment schedule. A combination of drugs probably results in a more effective treatment.
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Affiliation(s)
- H J Braam
- Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
| | - J H Schellens
- Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - H Boot
- Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - J W van Sandick
- Department of Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - C A Knibbe
- Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - D Boerma
- Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - B van Ramshorst
- Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands
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21
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Mehtala JG, Torregrosa-Allen S, Elzey BD, Jeon M, Kim C, Wei A. Synergistic effects of cisplatin chemotherapy and gold nanorod-mediated hyperthermia on ovarian cancer cells and tumors. Nanomedicine (Lond) 2014; 9:1939-55. [PMID: 24498890 DOI: 10.2217/nnm.13.209] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM The synergistic effects of gold nanorod (GNR)-mediated mild hyperthermia (MHT; 42-43°C) and cisplatin (CP) activity was evaluated against chemoresistant SKOV3 cells in vitro and with a tumor xenograft model. MATERIALS & METHODS In vitro studies were performed using CP at cytostatic concentrations (5 µM) and polyethylene glycol-stabilized GNRs, using near-infrared laser excitation for MHT. RESULTS The amount of polyethylene glycol-GNRs used for environmental MHT was 1 µg/ml, several times lower than the loadings used in tumor tissue ablation. GNR-mediated MHT increased CP-mediated cytotoxicity by 80%, relative to the projected additive effect, and flow cytometry analysis suggested MHT also enhanced CP-induced apoptosis. In a pilot in vivo study, systemically administered polyethylene glycol-GNRs generated sufficient levels of MHT to enhance CP-induced reductions in tumor volume, despite their heterogeneous distribution in tumor tissue. CONCLUSION These studies imply that effective chemotherapies can be developed in combination with low loadings of nanoparticles for localized MHT. Original submitted 6 July 2013; Revised submitted 20 October 2013.
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Affiliation(s)
- Jonathan G Mehtala
- Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA
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22
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Sekihara K, Harashima N, Tongu M, Tamaki Y, Uchida N, Inomata T, Harada M. Pifithrin-μ, an inhibitor of heat-shock protein 70, can increase the antitumor effects of hyperthermia against human prostate cancer cells. PLoS One 2013; 8:e78772. [PMID: 24244355 PMCID: PMC3828328 DOI: 10.1371/journal.pone.0078772] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 09/16/2013] [Indexed: 12/12/2022] Open
Abstract
Hyperthermia (HT) improves the efficacy of anti-cancer radiotherapy and chemotherapy. However, HT also inevitably evokes stress responses and increases the expression of heat-shock proteins (HSPs) in cancer cells. Among the HSPs, HSP70 is known as a pro-survival protein. In this study, we investigated the sensitizing effect of pifithrin (PFT)-μ, a small molecule inhibitor of HSP70, when three human prostate cancer cell lines (LNCaP, PC-3, and DU-145) were treated with HT (43°C for 2 h). All cell lines constitutively expressed HSP70, and HT further increased its expression in LNCaP and DU-145. Knockdown of HSP70 with RNA interference decreased the viability and colony-forming ability of cancer cells. PFT-μ decreased the viabilities of all cell lines at one-tenth the dose of Quercetin, a well-known HSP inhibitor. The combination therapy with suboptimal doses of PFT-μ and HT decreased the viability of cancer cells most effectively when PFT-μ was added immediately before HT, and this combination effect was abolished by pre-knockdown of HSP70, suggesting that the effect was mediated via HSP70 inhibition. The combination therapy induced cell death, partially caspase-dependent, and decreased proliferating cancer cells, with decreased expression of c-Myc and cyclin D1 and increased expression of p21WAF1/Cip, indicating arrest of cell growth. Additionally, the combination therapy significantly decreased the colony-forming ability of cancer cells compared to therapy with either alone. Furthermore, in a xenograft mouse model, the combination therapy significantly inhibited PC-3 tumor growth. These findings suggest that PFT-μ can effectively enhance HT-induced antitumor effects via HSP70 inhibition by inducing cell death and arrest of cell growth, and that PFT-μ is a promising agent for use in combination with HT to treat prostate cancer.
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Affiliation(s)
- Kazumasa Sekihara
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
- Department of Radiation Oncology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Nanae Harashima
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Miki Tongu
- Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Shimane, Japan
| | - Yukihisa Tamaki
- Department of Radiation Oncology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Nobue Uchida
- Department of Radiation Oncology, Tottori Prefectural Central Hospital, Tottori, Japan
| | - Taisuke Inomata
- Department of Radiation Oncology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Mamoru Harada
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
- * E-mail:
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23
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Lotti M, Busci LM, Campanati L, Catena F, Coccolini F, Bakrin N, Iaco PD, Ercolani G, Grosso G, Pisano M, Poiasina E, Rossetti D, Rossi M, Zamagni C, Bertoli P, Pinna AD, Frigerio L, Ansaloni L. Cytoreductive surgery and HIPEC after neoadjuvant chemotherapy for advanced epithelial ovarian cancer. World J Obstet Gynecol 2013; 2:167-175. [DOI: 10.5317/wjog.v2.i4.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 04/23/2013] [Accepted: 07/11/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To reduce postoperative complications and to make possible an optimal cytoreduction, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery has been applied with encouraging results.
METHODS: Between December 2009 and February 2012, patients with stage IIIC-IV epithelial ovarian cancer (EOC) underwent diagnostic laparoscopy, to assess the feasibility of optimal debulking surgery. The modified Fagotti score was applied to assess the feasibility of resection with zero residual tumor. Patients who were not candidate for upfront debulking surgery were submitted to NACT, then reassessed according to the RECIST 1.1 criteria and submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) if they showed clinical response or stable disease. The remaining cycles of adjuvant systemic chemotherapy (ASCT) were administered postoperatively, to complete 6 cycles of systemic chemotherapy.
RESULTS: Nine patients were included. Clinical response to NACT was complete in 3 patients and partial in 5 patients; one patient had stable disease. All patients underwent CRS resulting in CC0 disease prior to HIPEC. Average operative time was 510 min. Average intensive care unit stay was 2 d. Average postoperative hospital stay was 25 d. No postoperative mortality was observed. One patient experienced pelvic abscess. One patient refused ASCT. The remaining 8 patients started ASCT. Average time to chemotherapy was 36 d. All patients are alive, with an average follow up of 11 mo. Eight patients are disease-free at follow up.
CONCLUSION: HIPEC after CRS for advanced EOC is feasible with acceptable morbidity and mortality. NACT may increase the chance for achieving complete cytoreduction. Phase 3 studies are needed to determine the effects of HIPEC on survival.
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Roviello F, Caruso S, Neri A, Marrelli D. Treatment and prevention of peritoneal carcinomatosis from gastric cancer by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: overview and rationale. Eur J Surg Oncol 2013; 39:1309-16. [PMID: 24183797 DOI: 10.1016/j.ejso.2013.10.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 09/19/2013] [Accepted: 10/09/2013] [Indexed: 12/24/2022] Open
Abstract
Peritoneal carcinomatosis (PC) from gastric cancer is a condition with a very bleak prognosis. Most authors consider it to be a terminal disease and recommend palliative therapy only. Multimodal therapeutic approaches to PC have emerged in the last decades, combining cytoreductive surgery (CRS) and peritonectomy procedures with perioperative intraperitoneal chemotherapy (IPEC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). We reviewed the pertinent literature concerning the HIPEC modality both for the treatment of established PC and the prevention of peritoneal recurrence after potentially curative gastric cancer (GC) surgery. Basically, the two procedures relate to different aspects of GC and they are not comparable, since the latter has been used as an adjuvant when PC is still not macroscopically evident and the former has been exclusively used in advanced gastric cancer stages with peritoneal dissemination. Data supporting beneficial effects once gastric PC is already manifest is scarce and limited to few centres with specific experience in this field. Conversely, with regards to the peritoneal perfusion for preventing PC in high risk gastric cancer patients, there are phase III trials and meta-analysis which support beneficial effects resulting from the HIPEC procedure. To offer a baseline guide, we summarized the actual status and general outcome obtained by this multimodal technique, in association or not with CRS as treatment of advanced GC.
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Affiliation(s)
- F Roviello
- Department of Human Pathology and Oncology, Section of General Surgery and Surgical Oncology, University of Siena, Viale Bracci-Policlinico "Le Scotte", 53100 Siena, Italy
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25
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Giovinazzi S, Bellapu D, Morozov VM, Ishov AM. Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy. Cell Cycle 2013; 12:2598-607. [PMID: 23907120 DOI: 10.4161/cc.25591] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Microtubule-poisoning drugs, such as Paclitaxel (or Taxol, PTX), are powerful and commonly used anti-neoplastic agents for the treatment of several malignancies. PTX triggers cell death, mainly through a mitotic arrest following the activation of the spindle assembly checkpoint (SAC). Cells treated with PTX slowly slip from this mitotic block and die by mitotic catastrophe. However, cancer cells can acquire or are intrinsically resistant to this drug, posing one of the main obstacles for PTX clinical effectiveness. In order to override PTX resistance and increase its efficacy, we investigated both the enhancement of mitotic slippage and the block of mitotic exit. To test these opposing strategies, we used physiological hyperthermia (HT) to force exit from PTX-induced mitotic block and the anaphase-promoting complex/cyclosome (APC/C) inhibitor, proTAME, to block mitotic exit. We observed that application of HT on PTX-treated cells forced mitotic slippage, as shown by the rapid decline of cyclin B levels and by microscopy analysis. Similarly, HT induced mitotic exit in cells blocked in mitosis by other antimitotic drugs, such as Nocodazole and the Aurora A inhibitor MLN8054, indicating a common effect of HT on mitotic cells. On the other hand, proTAME prevented mitotic exit of PTX and MLN8054 arrested cells, prolonged mitosis, and induced apoptosis. In addition, we showed that proTAME prevented HT-mediated mitotic exit, indicating that stress-induced APC/C activation is necessary for HT-induced mitotic slippage. Finally, HT significantly increased PTX cytotoxicity, regardless of cancer cells' sensitivity to PTX, and this activity was superior to the combination of PTX with pro-TAME. Our data suggested that forced mitotic exit of cells arrested in mitosis by anti-mitotic drugs, such as PTX, can be a more successful anticancer strategy than blocking mitotic exit by inactivation of the APC/C.
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Affiliation(s)
- Serena Giovinazzi
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA
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Losa F, Barrios P, Salazar R, Torres-Melero J, Benavides M, Massuti T, Ramos I, Aranda E. Cytoreductive surgery and intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis from colorectal origin. Clin Transl Oncol 2013; 16:128-40. [DOI: 10.1007/s12094-013-1053-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 05/08/2013] [Indexed: 12/16/2022]
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Huang T, Gong W, Li X, Zou C, Jiang G, Li X, Feng D. Enhancement of osteosarcoma cell sensitivity to cisplatin using paclitaxel in the presence of hyperthermia. Int J Hyperthermia 2013; 29:248-55. [PMID: 23527624 DOI: 10.3109/02656736.2013.775511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE This paper aimed to evaluate the effects of a combination of paclitaxel and cisplatin on osteosarcoma (OS) cell lines in the presence of hyperthermia and to investigate the related mechanism. MATERIALS AND METHODS Two types of OS cell lines (OS732 and MG63) were treated with paclitaxel and cisplatin in the presence of hyperthermia. The survival rate was measured by MTT assay, and the clonogenic rate was measured by a clonogenic assay. The cellular changes were observed with an inverted phase contrast microscope and a fluorescence microscope. The apoptotic effect was analysed with flow cytometry (FCM). Fas expression by the OS cell lines was measured by western blot. Fas expression in OS tissue was measured by immunohistochemistry. RESULTS Our study indicated that 1 h after the application of a combination of 10 μg/mL paclitaxel and 5 μg/mL cisplatin to OS cells at 43 °C, the survival rate of the OS cells was 11.96%, which was significantly lower than when either 10 μg/mL paclitaxel (45.02%) or 5 μg/mL cisplatin (48.69%) was applied alone (p < 0.01). Additionally, the clonogenic assay demonstrated that the clonogenic survival rate in the OS cells of the combination group was lower than that in the individual groups. Moreover, the cellular changes and apoptosis rates indicated that apoptosis in the combined application group was much greater than when either drug was applied individually. Fas expression by OS cell lines was increased by the combination of paclitaxel and cisplatin under hyperthermic conditions. More importantly, our study revealed low Fas expression in OS, which better explained the up-regulation of Fas achieved by the combination of paclitaxel and cisplatin in the presence of hyperthermia. CONCLUSIONS The combination of paclitaxel and cisplatin increases the effects of thermochemotherapy on OS cell lines, primarily through the induction of apoptosis by the up-regulation of Fas expression.
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Affiliation(s)
- Tao Huang
- Department of Orthopaedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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de Bree E, Helm CW. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. Expert Rev Anticancer Ther 2013; 12:895-911. [PMID: 22845405 DOI: 10.1586/era.12.72] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The outcome of ovarian cancer remains poor with conventional therapy. Intraperitoneal chemotherapy has some advantages over systemic chemotherapy, including favorable pharmacokinetics and optimal treatment timing. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) provides improved exposure of the entire seroperitoneal surface to the agent and utilizes the direct cytoxic and drug-enhancing effect of hyperthermia. While standard normothermic, nonintraoperative, intraperitoneal chemotherapy has been demonstrated to be beneficial in randomized trials and meta-analyses, there are no data from randomized HIPEC trials available yet. Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. Data from ongoing randomized HIPEC trials to adequately answer the question of whether the addition of HIPEC actually prolongs survival in patients with peritoneal dissemination of primary and recurrent ovarian cancer are awaited in the near future.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete-University Hospital, PO Box 1352, 71110 Heraklion, Greece.
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Meenach SA, Shapiro JM, Hilt JZ, Anderson KW. Characterization of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2012; 24:1112-26. [PMID: 23683041 DOI: 10.1080/09205063.2012.741321] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Hyperthermia, the heating of tissue from 41 to 45 °C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n = 1000) methyl ether methacrylate and PEG (n = 400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response.
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Affiliation(s)
- Samantha A Meenach
- Department of Chemical & Materials Engineering, University of Kentucky, Lexington, KY 40506-0046, USA
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Huang T, Gong WH, Li XC, Zou CP, Jiang GJ, Li XH, Feng DP. Synergistic increase in the sensitivity of osteosarcoma cells to thermochemotherapy with combination of paclitaxel and etoposide. Mol Med Rep 2012; 6:1013-7. [PMID: 22948360 DOI: 10.3892/mmr.2012.1058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2012] [Accepted: 08/06/2012] [Indexed: 11/05/2022] Open
Abstract
Osteosarcoma is a malignant bone tumor which is found most commonly in adolescents and young adults. Local perfusion thermochemotherapy has long been proposed as an alternative strategy for the treatment of osteosarcoma. As a standard anticancer drug, paclitaxel plays a significant role in the treatment of a number of tumors; however, little is known concerning its ability to promote thermochemotherapy. The aim of this study was to evaluate the cytotoxic effects of a combination of paclitaxel and etoposide on an osteosarcoma cell line in the presence of hyperthermia and to investigate the related mechanism. Our study indicated that 1 h after the application of a combination of 10 µg/ml paclitaxel and 5 µg/ml etoposide to OS732 cells at 43˚C, the survival rate of the cells was 14.52% which was significantly lower than when either 10 µg/ml paclitaxel (45.83%) or 5 µg/ml etoposide (43.31%) was applied alone (P<0.01). Moreover, changes in cellular morphology and apoptotic rates indicated that the apoptosis-inducing effect of the combination was much stronger than that of either drug applied individually. Fas expression levels in the OS732 cells were increased by the combination of paclitaxel and etoposide in the presence of hyperthermia. Therefore, paclitaxel enhances the thermochemotherapy of the osteosarcoma cell line and this is primarily accomplished by the upregulation of Fas expression and the induction of apoptosis.
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Affiliation(s)
- T Huang
- Department of Orthopedics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
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Huang T, Gong WH, Li XC, Zou CP, Jiang GJ, Li XH, Feng DP. Induction of apoptosis by a combination of paclitaxel and carboplatin in the presence of hyperthermia. Asian Pac J Cancer Prev 2012; 13:81-5. [PMID: 22502718 DOI: 10.7314/apjcp.2012.13.1.081] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
PURPOSE To study enhancing effects of paclitaxel in the thermochemotherapy of osteosarcoma cell lines and related mechanisms. MATERIALS AND METHODS Paclitaxel and carboplatin were used alone or jointly on OS732 cell lines in the presence of hyperthermia. Inhibition of proliferation was measured by MTT assay and cellular changes were assessed with inverted phase contrast and fluorescence microscopy. Apoptosis was analyzed with flow cytometry (FCM) and Fas expression by immunocytochemistry. RESULTS At 43 degrees C, one hour after the application of 10 μg/ml paclitaxel and 5 μg/ml carboplatin on OS732 cells jointly, the survival rate was 15.8% which was significantly lower than with 10 μg/ml paclitaxel (45.8%) and 5 μg/ml carboplatin (47.7%) respectively (P<0.01). Moreover, changes of morphology and apoptotic rates indicated that the apoptosis-inducing effect of combined application was also much enhanced, as evident also regarding Fas expression. CONCLUSION Paclitaxel is conducive to thermochemotherapy of osteosarcoma cell lines, possibly accomplished by up-regulation of Fas expression with induction of apoptosis.
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Affiliation(s)
- Tao Huang
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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Meenach SA, Otu CG, Anderson KW, Hilt JZ. Controlled synergistic delivery of paclitaxel and heat from poly(β-amino ester)/iron oxide-based hydrogel nanocomposites. Int J Pharm 2012; 427:177-84. [DOI: 10.1016/j.ijpharm.2012.01.052] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 01/20/2012] [Accepted: 01/24/2012] [Indexed: 11/16/2022]
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Muller M, Chérel M, Dupré PF, Gouard S, Collet M, Classe JM. The Cytotoxic Effect of Combined Hyperthermia and Taxane Chemotherapy on Ovarian Cancer Cells: Results of an in vitro Study. Eur Surg Res 2012; 48:55-63. [DOI: 10.1159/000333393] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 07/20/2011] [Indexed: 11/19/2022]
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Is hyperthermic intraoperative peritoneal chemotherapy and systemic chemotherapy as effective as standard intraperitoneal chemotherapy: time for a prospective trial? Gynecol Oncol 2011; 122:207-8. [PMID: 21763889 DOI: 10.1016/j.ygyno.2011.06.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Kallas A, Pook M, Maimets M, Zimmermann K, Maimets T. Nocodazole treatment decreases expression of pluripotency markers Nanog and Oct4 in human embryonic stem cells. PLoS One 2011; 6:e19114. [PMID: 21559451 PMCID: PMC3084750 DOI: 10.1371/journal.pone.0019114] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Accepted: 03/25/2011] [Indexed: 01/06/2023] Open
Abstract
Nocodazole is a known destabiliser of microtubule dynamics and arrests cell-cycle at the G2/M phase. In the context of the human embryonic stem cell (hESC) it is important to understand how this arrest influences the pluripotency of cells. Here we report for the first time the changes in the expression of transcription markers Nanog and Oct4 as well as SSEA-3 and SSEA-4 in human embryonic cells after their treatment with nocodazole. Multivariate permeabilised-cell flow cytometry was applied for characterising the expression of Nanog and Oct4 during different cell cycle phases. Among untreated hESC we detected Nanog-expressing cells, which also expressed Oct4, SSEA-3 and SSEA-4. We also found another population expressing SSEA-4, but without Nanog, Oct4 and SSEA-3 expression. Nocodazole treatment resulted in a decrease of cell population positive for all four markers Nanog, Oct4, SSEA-3, SSEA-4. Nocodazole-mediated cell-cycle arrest was accompanied by higher rate of apoptosis and upregulation of p53. Twenty-four hours after the release from nocodazole block, the cell cycle of hESC normalised, but no increase in the expression of transcription markers Nanog and Oct4 was detected. In addition, the presence of ROCK-2 inhibitor Y-27632 in the medium had no effect on increasing the expression of pluripotency markers Nanog and Oct4 or decreasing apoptosis or the level of p53. The expression of SSEA-3 and SSEA-4 increased in Nanog-positive cells after wash-out of nocodazole in the presence and in the absence of Y-27632. Our data show that in hESC nocodazole reversible blocks cell cycle, which is accompanied by irreversible loss of expression of pluripotency markers Nanog and Oct4.
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Affiliation(s)
- Ade Kallas
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
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Antitumour efficacy of two paclitaxel formulations for hyperthermic intraperitoneal chemotherapy (HIPEC) in an in vivo rat model. Pharm Res 2011; 28:1653-60. [PMID: 21424162 DOI: 10.1007/s11095-011-0401-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Accepted: 02/14/2011] [Indexed: 12/14/2022]
Abstract
PURPOSE To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-β-cyclodextrin (Pac/RAME-β-CD) versus Taxol® at normo- and hyperthermic conditions in rats. METHODS Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment. RESULTS PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-β-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia. CONCLUSION Monitoring tumour growth via PET and MRI indicated that Pac/RAME-β-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.
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Ghosh S, De S, Chen Y, Sutton DC, Ayorinde FO, Dutta SK. Polychlorinated biphenyls (PCB-153) and (PCB-77) absorption in human liver (HepG2) and kidney (HK2) cells in vitro: PCB levels and cell death. ENVIRONMENT INTERNATIONAL 2010; 36:893-900. [PMID: 20723988 PMCID: PMC2949547 DOI: 10.1016/j.envint.2010.06.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 05/13/2010] [Accepted: 06/24/2010] [Indexed: 05/28/2023]
Abstract
An understanding of congener specific cellular absorption of PCBs is important to the study of the organ specific body burden of an individual and to their toxic effects. We have previously demonstrated that single PCB congeners induce cytotoxicity, as evidenced by decreased cellular viability and accelerated apoptotic death. There is very little, if any, information available on the differences in toxicity due to the nature of absorption of PCBs in different cells. To obtain such information human liver (HepG2) cells (in medium with 10% FBS) were exposed to 70 μM of both PCB-153 (non-coplanar hexachlorobiphenyl) and PCB-77 (coplanar tetrachlorobiphenyl), and human kidney (HK2) cells in serum free medium were exposed to 80 and 40 μM of PCB-153 and PCB-77 respectively, according to their LC(50) values in these cells. Medium and cells were collected separately at each time interval from 30 min to 48 h, and PCB concentrations were analyzed in both by GC-MS using biphenyl as an internal standard following hexane:acetone (50:50) extraction. We also performed trypan blue exclusion, DNA fragmentation and fluorescence microscopic studies in assessing cell viability and apoptotic cell death. About 40% of PCB-153 (35 μM, 50% of the maximum value) was detected in HepG2 cells within 30 min, and it reached its highest concentration at 6h (60 μM), concomitant with the PCB depletion in the medium (5 μM). For PCB-77, the highest concentrations within the cells were reached at 3h. However, the absorption levels of PCB-153 and PCB-77 in HK2 cells reached their peaks at 3 and 6h respectively. Exposure of human liver and kidney cells to PCB-153 and PCB-77 caused accelerated apoptotic cell death in a time-dependent manner. The studies demonstrated that (1) liver cells initiate the absorption of PCBs much faster than kidney cells; however, the concentration reaches its maximum level much earlier in kidney cells; (2) both PCB-153 and PCB-77 induced enhanced apoptotic death in liver and kidney cells; and (3) kidney cells are more vulnerable to PCBs based on the results of apoptosis and cellular viability, even with almost similar absorption or tissue burden of PCBs.
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Affiliation(s)
- Somiranjan Ghosh
- Department of Biology, Howard University, Washington DC 20059, USA
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Antoon JW, White MD, Meacham WD, Slaughter EM, Muir SE, Elliott S, Rhodes LV, Ashe HB, Wiese TE, Smith CD, Burow ME, Beckman BS. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology 2010; 151:5124-35. [PMID: 20861237 PMCID: PMC2954724 DOI: 10.1210/en.2010-0420] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.
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Affiliation(s)
- James W Antoon
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
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Teo M. Peritoneal-based Malignancies and Their Treatment. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2010. [DOI: 10.47102/annals-acadmedsg.v39n1p54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Introduction: Patients with peritoneal carcinomatosis (PC) usually have dismal prognoses, even with traditional systemic therapy. Peritonectomy or cytoreductive surgery (CRS) has been used to treat selected patients. It is also commonly used in the management of pseudomyxoma peritonei (PMP), often in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). Methods and Results: In the present review article, the indications for CRS and HIPEC are examined, along with its technical aspects, resulting morbidity and mortality. Patients with documented peritoneal carcinomatosis from colorectal and ovarian cancer or PMP, absence of extra-abdominal metastases and liver parenchymal metastases and with an ECOG performance status of <2 should be considered for CRS and HIPEC. Conclusion: It is important to recognise the role of and indications for CRS and HIPEC. Biologic factors of the disease and completeness of resection are important prognostic factors. Cytoreductive surgery, combined with intraperitoneal chemotherapy, can improve survival in selected patients with peritoneal-based malignancies.
Key words: Cytoreductive surgery, Intraperitoneal chemotherapy, Peritonectomy, Peritoneal carcinomatosis, Pseudomyxoma peritone
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Affiliation(s)
- Melissa Teo
- National Cancer Centre of Singapore, Singapore
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Polioudaki H, Kastrinaki MC, Papadaki HA, Theodoropoulos PA. Microtubule-interacting drugs induce moderate and reversible damage to human bone marrow mesenchymal stem cells. Cell Prolif 2009; 42:434-47. [PMID: 19486015 DOI: 10.1111/j.1365-2184.2009.00607.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES This study aimed to investigate molecular and cellular changes induced in human bone marrow mesenchymal stem cells (hMSCs) after treatment with microtubule-interacting agents and to estimate damage to the bone marrow microenvironment caused by chemotherapy. MATERIALS AND METHODS Using an in vitro hMSC culture system and biochemical and morphological approaches, we studied the effect of nocodazole and taxol(R) on microtubule and nuclear envelope organization, tubulin and p53 synthesis, cell cycle progression and proliferation and death of hMSCs isolated from healthy donors. RESULTS AND CONCLUSIONS Both nocodazole and taxol reduced hMSC proliferation and induced changes in the microtubular network and nuclear envelope morphology and organization. However, they exhibited only a moderate effect on cell death and partial arrest of hMSCs at G(2) but not at M phase of the cell cycle. Both agents induced expression of p53, exclusively localized in abnormally shaped nuclei, while taxol, but not nocodazole, increased synthesis of beta-tubulin isoforms. Cell growth rates and microtubule and nuclear envelope organization gradually normalized after transfer, in drug-free medium. Our data indicate that microtubule-interacting drugs reversibly inhibit proliferation of hMSCs; additionally, their cytotoxic action and effect on microtubule and nuclear envelope organization are moderate and reversible. We conclude that alterations in human bone marrow cells of patients under taxol chemotherapy are transient and reversible.
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Affiliation(s)
- H Polioudaki
- Department of Biochemistry, School of Medicine, University of Crete, Crete, Greece
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In vitro cytotoxicity of paclitaxel/beta-cyclodextrin complexes for HIPEC. Int J Pharm 2008; 367:148-54. [PMID: 18938234 DOI: 10.1016/j.ijpharm.2008.09.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Revised: 09/16/2008] [Accepted: 09/22/2008] [Indexed: 11/20/2022]
Abstract
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising strategy in the treatment of peritoneal carcinomatosis. To perform HIPEC, a tensioactive- and solvent-free paclitaxel formulation consisting of water-soluble paclitaxel/randomly methylated-beta-cyclodextrin (Pac/RAMEB) complexes was developed previously. Using MTT and SRB assays the cytotoxic activity of this formulation versus Taxol, was evaluated as well as the cytotoxicity of the different formulation excipients (RAMEB and Cremophor EL. The possible synergistic effect of heat and paclitaxel-based chemotherapy during HIPEC was also evaluated in vitro. The cytotoxicity assays revealed differences in viability between Cremophor EL and RAMEB treated cells of 40 and 50% for the CaCo-2 human and the CC531s rat colon cancer line, respectively, in favour of RAMEB. Despite the higher cytotoxicity of Cremophor EL, Pac/RAMEB complexes and Taxol were equipotent. Using the MTT and SRB assays the average difference in viability between both cell lines was below 10% and IC50 values showed no significant difference. Hyperthermia after drug administration (41 degrees C during 1h) had no effect on cell viability. These results indicated that it was possible to reformulate paclitaxel with a less cytotoxic vehicle while maintaining the cytotoxic activity of the formulation and that there is no synergism between paclitaxel and heat for in vitro cytotoxicity.
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al-Shammaa HAH, Li Y, Yonemura Y. Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol 2008; 14:1159-66. [PMID: 18300340 PMCID: PMC2690662 DOI: 10.3748/wjg.14.1159] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This article is to offer a concise review on the use of cytoreductive surgery (CRS) plus intraperitoneal hyperthermic chemotherapy (IPHC) for the treatment of peritoneal carcinomatosis (PC). Traditionally, PC was treated with systemic chemotherapy alone with very poor response and a median survival of less than 6 mo. With the establishment of several phase II studies, a new trend has been developed toward the use of CRS plus IPHC as a standard method for treating selected patients with PC, in whom sufficient cytoreduction could be achieved. In spite of the need for more high quality phase III studies, there is now a consensus among many surgical oncology experts throughout the world about the use of this new treatment strategy as standard care for colorectal cancer patients with PC. This review summarizes the current status and possible progress in future.
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de Bree E, Rosing H, Filis D, Romanos J, Melisssourgaki M, Daskalakis M, Pilatou M, Sanidas E, Taflampas P, Kalbakis K, Beijnen JH, Tsiftsis DD. Cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel: a clinical and pharmacokinetic study. Ann Surg Oncol 2008; 15:1183-92. [PMID: 18239973 DOI: 10.1245/s10434-007-9792-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2007] [Revised: 12/07/2007] [Accepted: 12/08/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before. METHODS Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m(2) paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients. RESULTS No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment. CONCLUSIONS HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, University Hospital, Crete University Medical School, P.O. Box 1352, 71 110, Herakleion, Greece.
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Ghosh S, De S, Dutta SK. Altered protein expressions in chronic PCB-153-induced human liver (HepG2) cells. Int J Toxicol 2007; 26:203-12. [PMID: 17564901 DOI: 10.1080/10915810701352648] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxic, endocrine disruption and reproductive abnormalities, including cancers. Chronic exposure to environmentally hazardous chemicals like PCBs is of great concern to human health. It has been reported earlier that apoptotic proteins change in rats under chronic PCB treatment. It is of importance to determine if chronically exposed human cells develop a different protein expression. In the present study, the authors chronically exposed metabolically competent human liver (HepG2) cells at 50 to 100 microM to examine the role of the well-known environmentally hazardous pollutant non-coplanar 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) to study cell death. After 12 weeks of exposure these cells showed significant changes in apoptotic death in subsequent trypan blue growth assay, fluorescence microscopy, DNA fragmentation, and immunoblotting studies. Interestingly, chronically exposed cells showed marked differences in apoptotic and/or death-related proteins (e.g., Bcl2, Bak, and the pro and active forms of caspase-9, which were up-regulated), in contrast to acutely exposed (i.e., 48-h PCB-153 exposed) cells, which maintained linear growth despite repeated exposures. Similarly, tumor suppressor protein p53, proto-oncogene c-myc, and cell cycle regulator protein p21 were also up-regulated compared to nonchronically exposed HepG2 Cells. The results indicated that PCB-153-induced chronic exposure significantly altered different apoptotic (e.g., Bcl2, Bak, caspase-3) and tumor suppressor (e.g., p21, p53, and c-myc) proteins in the cellular model. These results suggest that chronic exposure to PCB-153 can induce cell survival by altering several apoptotic and tumor suppressor proteins.
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de Bree E, Tsiftsis DD. Experimental and pharmacokinetic studies in intraperitoneal chemotherapy: from laboratory bench to bedside. RECENT RESULTS IN CANCER RESEARCH. FORTSCHRITTE DER KREBSFORSCHUNG. PROGRES DANS LES RECHERCHES SUR LE CANCER 2007; 169:53-73. [PMID: 17506249 DOI: 10.1007/978-3-540-30760-0_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Herakleion, Greece
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de Bree E, Tsiftsis DD. Principles of perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis. Recent Results Cancer Res 2007; 169:39-51. [PMID: 17506248 DOI: 10.1007/978-3-540-30760-0_4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Herakleion, Greece
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