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El-Ghiaty MA, Alqahtani MA, El-Mahrouk SR, Isse FA, Alammari AH, El-Kadi AOS. Alteration of Hepatic Cytochrome P450 Expression and Arachidonic Acid Metabolism by Arsenic Trioxide (ATO) in C57BL/6 Mice. Biol Trace Elem Res 2025; 203:1000-1015. [PMID: 38758479 DOI: 10.1007/s12011-024-04225-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/05/2024] [Indexed: 05/18/2024]
Abstract
The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effect of ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients.
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Affiliation(s)
- Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Sara R El-Mahrouk
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Fadumo A Isse
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Ahmad H Alammari
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada.
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El-Mahrouk SR, El-Ghiaty MA, Alqahtani MA, El-Kadi AOS. Arsenic Trioxide (ATO III) Induces NAD(P)H Quinone Oxidoreductase 1 (NQO1) Expression in Hepatic and Extrahepatic Tissues of C57BL/6 Mice. Chem Res Toxicol 2024; 37:2040-2051. [PMID: 39630573 DOI: 10.1021/acs.chemrestox.4c00422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Arsenic trioxide (ATOIII) has emerged as a potent therapeutic agent for acute promyelocytic leukemia (APL), yet its clinical application is often limited by significant adverse effects. This study investigates the molecular mechanisms underlying ATOIII's impact on cellular detoxification pathways, focusing on the regulation of NAD(P)H/quinone oxidoreductase (NQO1), a crucial enzyme in maintaining cellular homeostasis and cancer prevention. We explored ATOIII's effects on NQO1 expression in C57BL/6 mice and Hepa-1c1c7 cells, both independently and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a known NQO1 inducer. Our findings revealed that ATOIII significantly increased NQO1 expression in hepatic and extrahepatic tissues, as well as in Hepa-1c1c7 cells, at mRNA, protein, and activity levels. This upregulation occurred both in the presence and absence of TCDD. Mechanistically, we demonstrated that ATOIII promotes the nuclear translocation of both nuclear factor erythroid 2-related factor-2 (NRF2) and aryl hydrocarbon receptor (AHR) transcription factors. Furthermore, ATOIII exposure increased antioxidant response element (ARE)-driven reporter gene activity, indicating a transcriptional mechanism of NQO1 induction. Notably, gene silencing experiments confirmed the critical roles of both NRF2 and AHR in mediating ATOIII-induced NQO1 expression. In conclusion, ATOIII exposure is found to upregulate the NQO1 enzyme through a transcriptional mechanism via AHR- and NRF2- dependent mechanisms, offering valuable insights into its therapeutic mechanisms.
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Affiliation(s)
- Sara R El-Mahrouk
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
- Faculty of Pharmacy, Tanta University, Gharbia, Tanta 31111, Egypt
| | - Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
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Balarastaghi S, Rezaee R, Hayes AW, Yarmohammadi F, Karimi G. Mechanisms of Arsenic Exposure-Induced Hypertension and Atherosclerosis: an Updated Overview. Biol Trace Elem Res 2023; 201:98-113. [PMID: 35167029 DOI: 10.1007/s12011-022-03153-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/08/2022] [Indexed: 01/11/2023]
Abstract
Arsenic is an abundant element in the earth's crust. In the environment and within the human body, this toxic element can be found in both organic and inorganic forms. Chronic exposure to arsenic can predispose humans to cardiovascular diseases including hypertension, stroke, atherosclerosis, and blackfoot disease. Oxidative damage induced by reactive oxygen species is a major player in arsenic-induced toxicity, and it can affect genes expression, inflammatory responses, and/or nitric oxide homeostasis. Exposure to arsenic in drinking water can lead to vascular endothelial dysfunction which is reflected by an imbalance between vascular relaxation and contraction. Arsenic has been shown to inactivate endothelial nitric oxide synthase leading to a reduction of the generation and bioavailability of nitric oxide. Ultimately, these effects increase the risk of vascular diseases such as hypertension and atherosclerosis. The present article reviews how arsenic exposure contributes to hypertension and atherosclerosis development.
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Affiliation(s)
- Soudabeh Balarastaghi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Rezaee
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - A Wallace Hayes
- Center for Environmental Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, USA
| | - Fatemeh Yarmohammadi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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El-Ghiaty MA, Alqahtani MA, El-Kadi AOS. Down-regulation of hepatic cytochromes P450 1A1 and 1A2 by arsenic trioxide (ATO) in vivo and in vitro: A role of heme oxygenase 1. Chem Biol Interact 2022; 364:110049. [PMID: 35872050 DOI: 10.1016/j.cbi.2022.110049] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/03/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
Abstract
Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 μg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 μM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination.
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Affiliation(s)
- Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
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Zhao Y, Yao H, Yang K, Han S, Chen S, Li Y, Chen S, Huang K, Lian G, Li J. Arsenic Trioxide-loaded nanoparticles Enhance the Chemosensitivity of Gemcitabine in Pancreatic Cancer via Reversal of Pancreatic Stellate Cells Desmoplasia through Targeting AP4/Galectin-1 Pathway. Biomater Sci 2022; 10:5989-6002. [DOI: 10.1039/d2bm01039a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Pancreatic stellate cell (PSCs) constitutes the fibrotic tumor microenvironment composed of the stroma matrix, which blocks the penetration of Gemcitabine (GEM) in pancreatic adenocarcinoma (PDAC) and results in chemoresistance. We...
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Zhang J, Ma Y, Zhang Y, Niu S, Chu M, Zhang Z. Angiogenesis is Inhibited by Arsenic Trioxide Through Downregulation of the CircHIPK3/miR-149-5p/FOXO1/VEGF Functional Module in Rheumatoid Arthritis. Front Pharmacol 2021; 12:751667. [PMID: 34776969 PMCID: PMC8579003 DOI: 10.3389/fphar.2021.751667] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/15/2021] [Indexed: 01/22/2023] Open
Abstract
Angiogenesis is a crucial event in the pathogenesis of rheumatoid arthritis (RA). Arsenic trioxide (ATO, As2O3) has been reported to inhibit synovial angiogenesis via the vascular endothelial growth factor (VEGF)-centered functional module. However, the exact mechanisms of ATO on VEGF modulation remain unclear. Circular RNAs (circRNAs) are emerging as important regulators in RA, and the detailed mechanisms remain largely unknown. Here, we reported a circRNA (circHIPK3), the expression of which was significantly increased in RA fibroblast-like synoviocytes (RA-FLS) after TNF-α induction. Moreover, VEGF content in the supernatants of a RA-FLS and human dermal microvascular endothelial cell (HDMEC) co-culture as well as in RA-FLS co-cultured was significantly elevated in accordance with circHIPK3 levels. This increased VEGF expression may significantly upregulate endothelial tube formation and transwell migration, as well as microvessel sprouting in the ex vivo aortic ring assay. CircHIPK3 was further illustrated to be a sponge for the forkhead box transcription factor O1 (FOXO1)-targeting miR-149-5p, leading to the changing expression of the downstream VEGF. These networked factors mainly form a functional module regulating angiogenesis in RA-FLS, and the expression of this functional module could be significantly downregulated by ATO with a consistently reduced vascularity in vitro. In the collagen-induced arthritis (CIA) mice model, an intra-articular injection of the adeno-associated virus-si-circHIPK3 or ATO was demonstrated to alleviate the synovial VEGF expression and arthritis severity respectively. Thus, we elucidate a previously unknown mechanism between circRNAs and RA, and ATO has a significant protective effect on RA-FLS and CIA synovium via its inhibition of the angiogenic functional module of circHIPK3/miR-149-5p/FOXO1/VEGF, suggesting great potential for the combination therapy of ATO with circHIPK3 silencing.
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Affiliation(s)
- Juan Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yeye Ma
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yue Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Sijia Niu
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Maolin Chu
- Department of Urology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Zhiyi Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
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Liu L, O’Kelly D, Schuetze R, Carlson G, Zhou H, Trawick ML, Pinney KG, Mason RP. Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors. Molecules 2021; 26:2551. [PMID: 33925707 PMCID: PMC8125421 DOI: 10.3390/molecules26092551] [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: 03/27/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.
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Affiliation(s)
- Li Liu
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Devin O’Kelly
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Regan Schuetze
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Graham Carlson
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Heling Zhou
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Mary Lynn Trawick
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Kevin G. Pinney
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Ralph P. Mason
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
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Wu Q, Chen X, Wang P, Wu Q, Qi X, Han X, Chen L, Meng X, Xu K. Delivery of Arsenic Trioxide by Multifunction Nanoparticles To Improve the Treatment of Hepatocellular Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2020; 12:8016-8029. [PMID: 31997633 DOI: 10.1021/acsami.9b22802] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Arsenic trioxide (ATO) is effective in the treatment of hematological malignancies and solid tumors. However, its toxicity and side effects are severe, posing an obstacle in its clinical application. A controlled-release ATO carrier with mitochondrial targeting was constructed in this study. The safety and efficacy in vitro were investigated using a hemolysis test, cytotoxicity, proliferation, migration, apoptosis, and other changes in cell behavior. The safety and efficacy were further evaluated in vivo by hematoxylin-eosin staining, terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling staining, and blood testing in tumor-bearing mice. Immunohistochemically and western blotting experiments were conducted to explore the mechanism of combination therapy of material-based chemotherapy and microwave hyperthermia in vitro. We demonstrated that the nano-zirconia (ZrO2) loading platform may be used to administer the ATO, with local precision-controlled release and mitochondrial targeting. Furthermore, we showed the safety of this approach for delivering high doses of ATO. In addition, we explored this new method in combination with in vitro microwave heat therapy, providing a potentially novel intravenous approach to chemotherapy. We described a new non-invasive treatment that improved the efficacy of ATO chemotherapy against hepatocellular carcinoma through nano-ZrO2 carriers.
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MESH Headings
- Animals
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Arsenic Trioxide/administration & dosage
- Arsenic Trioxide/pharmacology
- Arsenic Trioxide/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Delayed-Action Preparations
- Drug Carriers/chemistry
- Drug Liberation
- Hep G2 Cells
- Humans
- Hyperthermia, Induced/instrumentation
- Hyperthermia, Induced/methods
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Male
- Membrane Potential, Mitochondrial/drug effects
- Mice
- Microscopy, Electron, Scanning
- Microscopy, Electron, Transmission
- Mitochondria/drug effects
- Nanoparticles/chemistry
- Nanoparticles/ultrastructure
- Particle Size
- Xenograft Model Antitumor Assays
- Zirconium/chemistry
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Affiliation(s)
- Qirun Wu
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xiaowei Chen
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Peng Wang
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Qiong Wu
- Laboratory of Controllable Preparation and Application of Nanomaterials, Laboratory of Cryogenics, Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Beijing 100190 , China
| | - Xun Qi
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xiangjun Han
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Lufeng Chen
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Laboratory of Cryogenics, Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Beijing 100190 , China
| | - Ke Xu
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
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Sobel MH, Sanchez TR, Jones MR, Kaufman JD, Francesconi KA, Blaha MJ, Vaidya D, Shimbo D, Gossler W, Gamble MV, Genkinger JM, Navas‐Acien A. Rice Intake, Arsenic Exposure, and Subclinical Cardiovascular Disease Among US Adults in MESA. J Am Heart Assoc 2020; 9:e015658. [PMID: 32067593 PMCID: PMC7070216 DOI: 10.1161/jaha.119.015658] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/11/2022]
Abstract
Background Arsenic-related cardiovascular effects at exposure levels below the US Environmental Protection Agency's standard of 10 μg/L are unclear. For these populations, food, especially rice, is a major source of exposure. We investigated associations of rice intake, a marker of arsenic exposure, with subclinical cardiovascular disease (CVD) markers in a multiethnic population. Methods and Results Between 2000 and 2002, MESA (Multi-Ethnic Study of Atherosclerosis) enrolled 6814 adults without clinical CVD. We included 5050 participants with baseline data on rice intake and markers of 3 CVD domains: inflammation (hsCRP [high-sensitivity C-reactive protein], interleukin-6, and fibrinogen), vascular function (aortic distensibility, carotid distensibility, and brachial flow-mediated dilation), and subclinical atherosclerosis at 3 vascular sites (carotid intima-media thickness, coronary artery calcification, and ankle-brachial index). We also evaluated endothelial-related biomarkers previously associated with arsenic. Rice intake was assessed by food frequency questionnaire. Urinary arsenic was measured in 310 participants. A total of 13% of participants consumed ≥1 serving of rice/day. Compared with individuals consuming <1 serving of rice/week, ≥1 serving of rice/day was not associated with subclinical markers after demographic, lifestyle, and CVD risk factor adjustment (eg, geometric mean ratio [95% CI] for hsCRP, 0.98 [0.86-1.11]; aortic distensibility, 0.99 [0.91-1.07]; and carotid intima-media thickness, 0.98 [0.91-1.06]). Associations with urinary arsenic were similar to those for rice intake. Conclusions Rice intake was not associated with subclinical CVD markers in a multiethnic US population. Research using urinary arsenic is needed to assess potential CVD effects of low-level arsenic exposure. Understanding the role of low-level arsenic as it relates to subclinical CVD may contribute to CVD prevention and control.
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Affiliation(s)
- Marisa H. Sobel
- Department of Environmental Health ScienceColumbia UniversityNew YorkNY
| | | | - Miranda R. Jones
- Department of EpidemiologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreMD
| | | | | | | | | | | | | | - Mary V. Gamble
- Department of Environmental Health ScienceColumbia UniversityNew YorkNY
| | | | - Ana Navas‐Acien
- Department of Environmental Health ScienceColumbia UniversityNew YorkNY
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Jenkins SV, Nedosekin DA, Shaulis BJ, Wang T, Jamshidi-Parsian A, Pollock ED, Chen J, Dings RP, Griffin RJ. Enhanced Photothermal Treatment Efficacy and Normal Tissue Protection via Vascular Targeted Gold Nanocages. Nanotheranostics 2019; 3:145-155. [PMID: 31008023 PMCID: PMC6470343 DOI: 10.7150/ntno.32395] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/14/2019] [Indexed: 01/22/2023] Open
Abstract
A major challenge in photothermal treatment is generating sufficient heat to eradicate diseased tissue while sparing normal tissue. Au nanomaterials have shown promise as a means to achieve highly localized photothermal treatment. Toward that end, the synthetic peptide anginex was conjugated to Au nanocages. Anginex binds to galectin-1, which is highly expressed in dividing endothelial cells found primarily in the tumor vasculature. The skin surface temperature during a 10 min laser exposure of subcutaneous murine breast tumors did not exceed 43°C and no normal tissue damage was observed, yet a significant anti-tumor effect was observed when laser was applied 24 h post-injection of targeted nanocages. Untargeted particles showed little effect in immunocompetent, tumor-bearing mice under these conditions. Photoacoustic, photothermal, and ICP-MS mapping of harvested tissue showed distribution of particles near the vasculature throughout the tumor. This uptake pattern within the tumor combined with a minimal overall temperature rise were nonetheless sufficient to induce marked photothermal efficacy and evidence of tumor control. Importantly, this evidence suggests that bulk tumor temperature during treatment does not correlate with treatment outcome, which implies that targeted nanomedicine can be highly effective when closely bound/distributed in and around the tumor endothelium and extensive amounts of direct tumor cell binding may not be a prerequisite of effective photothermal approaches.
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Affiliation(s)
- Samir V. Jenkins
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR,✉ Corresponding author: Dr. Samir V. Jenkins, , Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham, Mail Slot #771, Little Rock, AR 72205, USA
| | - Dmitry A. Nedosekin
- Department of Otolaryngology and Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Barry J. Shaulis
- Trace Element and Radiogenic Isotope Lab, University of Arkansas, Fayetteville, AR
| | - Tengjiao Wang
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR
| | - Azemat Jamshidi-Parsian
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Erik D. Pollock
- Trace Element and Radiogenic Isotope Lab, University of Arkansas, Fayetteville, AR
| | - Jingyi Chen
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR
| | - Ruud P.M. Dings
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Robert J. Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR
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Zhang J, Li C, Zheng Y, Lin Z, Zhang Y, Zhang Z. Inhibition of angiogenesis by arsenic trioxide via TSP-1-TGF-β1-CTGF-VEGF functional module in rheumatoid arthritis. Oncotarget 2017; 8:73529-73546. [PMID: 29088724 PMCID: PMC5650279 DOI: 10.18632/oncotarget.19867] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 07/11/2017] [Indexed: 01/25/2023] Open
Abstract
Angiogenesis is a critical factor for rheumatoid arthritis (RA). Although anti-TNF biologics work effectively on some RA patients, concerns have been raised about the possible increased development of malignancies alongside such treatments. Arsenic trioxide (As2O3) has attracted worldwide attention and has been reported to treat some cancers. However, the effects of As2O3 on angiogenesis in the RA synovium remain unclear. Here, we report a systematic increased expression of TSP-1, TGF-β1, CTGF and VEGF in supernatants of a RA fibroblast-like synoviocytes (RA-FLS) and human dermal microvascular endothelial cells (HDMECs) co-culture compared with those from a normal human fibroblast-like synoviocytes (NH-FLS) and HDMECs co-culture. This increased expression may up-regulate endothelial tube formation and transwell migration, as well as microvessel sprouting in ex vivo aortic ring assay. These networked angiogenic factors mainly form a functional module regulating angiogenesis in the RA synovium. We show that As2O3 inhibits angiogenesis in the collagen-induced arthritis (CIA) synovium and consequently arthritis severity via significant suppression of TSP-1, TGF-β1, CTGF and VEGF expression in the CIA synovium, plus in the RA-FLS and HDMECs co-culture as well as NH-FLS and HDMECs co-culture system along with the presence or absence of TNF-α treatment. Thus As2O3 has a significant anti-angiogenesis effect on the RA-FLS and CIA synovium via its inhibition of the RA angiogenic functional module of TSP-1, TGF-β1, CTGF and VEGF and may have a potential for treating RA beyond cancer therapy.
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Affiliation(s)
- Juan Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
| | - Chunling Li
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
| | - Yining Zheng
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
| | - Zhiguo Lin
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
| | - Yue Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
| | - Zhiyi Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China
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12
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Griffin RJ, Williams BW, Roberts KP, Swanlund DJ, Bischof JC. Assessing pH and Oxygenation in Cryotherapy-induced Cytotoxicity and Tissue Response to Freezing. Technol Cancer Res Treat 2016; 3:245-51. [PMID: 15161317 DOI: 10.1177/153303460400300302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The microenvironmental pH and oxygenation is known to influence tumor cell response to heat, radiation, photodynamic and even chemotherapy. We have studied the previously untested influence of acidity and hypoxia on tumor and endothelial cell sensitivity to freezing. In addition, we have measured changes in oxygenation in vivo in murine FSaII fibrosarcomas after freeze injury. A low pH or low oxygenation environment was found to increase the sensitivity of tumor and endothelial cells to freezing at −20° C or −40° C in vitro. However, low pH and low oxygenation combined did not further increase cryosensitivity of the cells. In vivo, tumor oxygenation after freeze injury was studied immediately or 1–3 days after a standard freezing protocol was applied to FSaII tumors ranging from 250–500 mm3 grown in the rear-limb of C3H mice. Tumor oxygenation at the edge of the iceball was found to transiently increase 1–2 hours after freezing. At 1–3 days after freezing, a treatment that delayed FSaII tumor growth by approximately 1.5-fold, the mean tumor oxygenation was significantly increased by up to 2.5-fold from a control level of 5 mmHg partial pressure of oxygen (pO2), especially at the periphery of the tumor. We conclude that manipulation of pH or oxygenation has potential to increase the anti-tumor effects of minimally invasive cryosurgical techniques. Furthermore, the dynamic changes in oxygenation after freeze injury in vivo suggests value in combining cryotherapy with treatments dependent on oxygenation levels. Ultimately, these may be routes to more reliable treatment response with fewer recurrences.
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Affiliation(s)
- Robert J Griffin
- University of Minnesota, Department of Therapeutic Radiology, 420 Delaware St. SE, MMC 494, Minneapolis, MN 55455, USA.
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13
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Horsman MR. Realistic biological approaches for improving thermoradiotherapy. Int J Hyperthermia 2015; 32:14-22. [DOI: 10.3109/02656736.2015.1099169] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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14
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Horsman MR. Therapeutic potential of using the vascular disrupting agent OXi4503 to enhance mild temperature thermoradiation. Int J Hyperthermia 2015; 31:453-9. [PMID: 25915829 DOI: 10.3109/02656736.2015.1024289] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE The response of tissues to radiation with mild temperature hyperthermia is dependent on the interval between the two modalities. This study investigated the effect that the vascular disrupting agent OXi4503 had on this time-interval interaction. METHODS The normal right rear foot of female CDF1 mice or foot-implanted C3H mammary carcinomas were locally irradiated (230 kV X-rays) and heated (41.5 °C for 60 min) by foot immersion in a water bath. OXi4503 (50 mg/kg) was injected intraperitoneally 1.5 h before irradiating. Irradiation was performed either in the middle of the heating period (simultaneous treatment) or at 1 or 4 h prior to starting the heating (sequential treatments). Response was the percentage of mice showing local tumour control at 90 days or skin moist desquamation between days 11-23. From the radiation dose response curves the dose producing tumour control (TCD(50)) or moist desquamation (MDD50) in 50% of mice was calculated. RESULTS The TCD(50) and MDD50 values for radiation alone were 54 Gy and 29 Gy, respectively. Simultaneously heating the tissues enhanced radiation response, the respective TCD(50) and MDD50 values being significantly (chi-square test, p < 0.05) reduced to 33 Gy and 14 Gy. A smaller enhancement was obtained with a sequential treatment in both tissues. OXi4503 enhanced the radiation response of tumour and skin. Combined with radiation and heat, the only effect was in tumours where OXi4503 prevented the decrease in sensitisation seen with the sequential treatment. CONCLUSION Combining OXi4503 with a sequential radiation and heat treatment resulted in a 1.4-fold therapeutic gain.
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Affiliation(s)
- Michael R Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital , Aarhus , Denmark
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15
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16
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Siemann DW, Horsman MR. Targeting the tumor vasculature: a strategy to improve radiation therapy. Expert Rev Anticancer Ther 2014; 4:321-7. [PMID: 15056061 DOI: 10.1586/14737140.4.2.321] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A continuously expanding vasculature is an essential requirement of a growing neoplastic mass. The blood-vessel network provides not only nutritional support and waste product management, but also offers opportunities for the secondary spread of tumor cells. Given its crucial role in tumor development, growth and spread, considerable efforts have been spent on developing therapeutic strategies that compromise the growth and/or function of the tumor neovasculature. Two primary approaches are being pursued. Angiogenic inhibitors seek to interrupt the process of angiogenesis to prevent new tumor blood-vessel formation. Vascular disrupting agents aim to cause direct damage to the existing tumor endothelium. Lead agents in both categories have now advanced into clinical trials. Still, their greatest utility may ultimately lie in combinations with conventional anticancer therapies. Indeed, the application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.
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Affiliation(s)
- Dietmar W Siemann
- Department of Radiation Oncology, Shands Cancer Center, University of Florida, 2000 SW Archer Road, Gainesville, FL 32610, USA.
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Wu J, Ji Z, Liu H, Liu Y, Han D, Shi C, Shi C, Wang C, Yang G, Chen X, Shen C, Li H, Bi Y, Zhang D, Zhao S. Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway. Toxicol Lett 2013; 220:61-9. [PMID: 23542114 DOI: 10.1016/j.toxlet.2013.03.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 03/12/2013] [Accepted: 03/20/2013] [Indexed: 12/31/2022]
Abstract
Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway.
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Affiliation(s)
- Jianing Wu
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Arsenic Trioxide as a Vascular Disrupting Agent: Synergistic Effect with Irinotecan on Tumor Growth Delay in a CT26 Allograft Model. Transl Oncol 2013; 6:83-91. [PMID: 23418620 DOI: 10.1593/tlo.12322] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 11/22/2012] [Accepted: 11/25/2012] [Indexed: 11/18/2022] Open
Abstract
The mechanism of action of arsenic trioxide (ATO) has been shown to be complex, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects. Among these mechanisms of action, ATO has been shown to cause acute vascular shutdown and massive tumor necrosis in a murine solid tumor model like vascular disrupting agent (VDA). However, relatively little is understood about this VDA-like property and its potential utility in developing clinical regimens. We focused on this VDA-like action of ATO. On the basis of the endothelial cell cytotoxicity assay and tubulin polymerization assay, we observed that higher concentrations and longer treatment with ATO reduced the level of α- and β-tubulin and inhibited the polymerization of tubulin. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced murine CT26 colon carcinoma grown in female BALB/c mice. A single injection of ATO intraperitoneally displayed central necrosis of the tumor tissue by 24 hours. T1-weighted dynamic contrast-enhanced magnetic resonance image revealed a significant decrease in tumor enhancement in the ATO-treated group. Similar to other VDAs, ATO treatment alone did not delay the progression of tumor growth; however, ATO treatment after injection of other cytotoxic agent (irinotecan) showed significant additive antitumor effect compared to control and irinotecan alone therapy. In summary, our data demonstrated that ATO acts as a VDA by means of microtubule depolymerization. It exhibits significant vascular shutdown activity in CT26 allograft model and enhances antitumor activity when used in combination with another cytotoxic chemotherapeutic agent.
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Alhasan MK, Liu L, Lewis MA, Magnusson J, Mason RP. Comparison of optical and power Doppler ultrasound imaging for non-invasive evaluation of arsenic trioxide as a vascular disrupting agent in tumors. PLoS One 2012; 7:e46106. [PMID: 23029403 PMCID: PMC3460997 DOI: 10.1371/journal.pone.0046106] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 08/28/2012] [Indexed: 01/13/2023] Open
Abstract
Small animal imaging provides diverse methods for evaluating tumor growth and acute response to therapy. This study compared the utility of non-invasive optical and ultrasound imaging to monitor growth of three diverse human tumor xenografts (brain U87-luc-mCherry, mammary MCF7-luc-mCherry, and prostate PC3-luc) growing in nude mice. Bioluminescence imaging (BLI), fluorescence imaging (FLI), and Power Doppler ultrasound (PD US) were then applied to examine acute vascular disruption following administration of arsenic trioxide (ATO). During initial tumor growth, strong correlations were found between manual caliper measured tumor volume and FLI intensity, BLI intensity following luciferin injection, and traditional B-mode US. Administration of ATO to established U87 tumors caused significant vascular shutdown within 2 hrs at all doses in the range 5 to 10 mg/kg in a dose dependant manner, as revealed by depressed bioluminescent light emission. At lower doses substantial recovery was seen within 4 hrs. At 8 mg/kg there was >85% reduction in tumor vascular perfusion, which remained depressed after 6 hrs, but showed some recovery after 24 hrs. Similar response was observed in MCF7 and PC3 tumors. Dynamic BLI and PD US each showed similar duration and percent reductions in tumor blood flow, but FLI showed no significant changes during the first 24 hrs. The results provide further evidence for comparable utility of optical and ultrasound imaging for monitoring tumor growth, More specifically, they confirm the utility of BLI and ultrasound imaging as facile assays of the vascular disruption in solid tumors based on ATO as a model agent.
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Affiliation(s)
| | | | | | - Jennifer Magnusson
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Ralph P. Mason
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- * E-mail:
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20
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Wu F, Jasmine F, Kibriya MG, Liu M, Wójcik O, Parvez F, Rahaman R, Roy S, Paul-Brutus R, Segers S, Slavkovich V, Islam T, Levy D, Mey JL, van Geen A, Graziano JH, Ahsan H, Chen Y. Association between arsenic exposure from drinking water and plasma levels of cardiovascular markers. Am J Epidemiol 2012; 175:1252-61. [PMID: 22534204 PMCID: PMC3372314 DOI: 10.1093/aje/kwr464] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 11/14/2011] [Indexed: 01/20/2023] Open
Abstract
The authors conducted a cross-sectional study to assess the relation between arsenic exposure from drinking water and plasma levels of markers of systemic inflammation and endothelial dysfunction (matrix metalloproteinase-9, myeloperoxidase, plasminogen activator inhibitor-1, soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble vascular adhesion molecule-1 (VCAM-1)) using baseline data from 668 participants (age, >30 years) in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2007-2008). Both well water arsenic and urinary arsenic were positively associated with plasma levels of soluble VCAM-1. For every 1-unit increase in log-transformed well water arsenic (ln μg/L) and urinary arsenic (ln μg/g creatinine), plasma soluble VCAM-1 was 1.02 (95% confidence interval: 1.01, 1.03) and 1.04 (95% confidence interval: 1.01, 1.07) times greater, respectively. There was a significant interaction between arsenic exposure and higher body mass index, such that the increased levels of plasminogen activator inhibitor-1 and soluble VCAM-1 associated with arsenic exposure were stronger among people with higher body mass index. The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation and endothelial dysfunction that could be modified by body mass index and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Yu Chen
- Correspondence to Dr. Yu Chen, Departments of Environmental Medicine and Medicine, New York University School of Medicine, 650 First Avenue, Room 510, New York, NY 10016 (e-mail: )
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Su Y, Wang X, Xu W, Xue L, He C, Yang D, An R. Arsenic Trioxide Increases the Sensitivity of 786–0 Renal Carcinoma Cells to Radiotherapy. Cancer Invest 2012; 30:114-8. [DOI: 10.3109/07357907.2011.640652] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Vascular disrupting agent arsenic trioxide enhances thermoradiotherapy of solid tumors. JOURNAL OF ONCOLOGY 2012; 2012:934918. [PMID: 22272199 PMCID: PMC3261488 DOI: 10.1155/2012/934918] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Revised: 08/23/2011] [Accepted: 09/06/2011] [Indexed: 11/17/2022]
Abstract
Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disruption and augmentation of thermal or radiotherapy effect against solid tumors. These results suggested that a trimodality approach of radiation, ATO, and local hyperthermia may have potent therapeutic efficacy against solid tumors. Here, we report the antitumor effect of hypofractionated radiation followed by ATO administration and local 42.5 °C hyperthermia and the effects of cisplatin and thermoradiotherapy. We found that the therapeutic efficacy of ATO-based thermoradiotherapy was equal or greater than that of cisplatin-based thermoradiotherapy, and marked evidence of in vivo apoptosis and tumor necrosis were observed in ATO-treated tumors. We conclude that ATO-based thermoradiotherapy is a powerful means to control tumor growth by using vascular disruption to augment the effects of thermal and radiation therapy.
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Shenoi MM, Shah NB, Griffin RJ, Vercellotti GM, Bischof JC. Nanoparticle preconditioning for enhanced thermal therapies in cancer. Nanomedicine (Lond) 2011; 6:545-63. [PMID: 21542691 DOI: 10.2217/nnm.10.153] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Nanoparticles show tremendous promise in the safe and effective delivery of molecular adjuvants to enhance local cancer therapy. One important form of local cancer treatment that suffers from local recurrence and distant metastases is thermal therapy. In this article, we review a new concept involving the use of nanoparticle-delivered adjuvants to 'precondition' or alter the vascular and immunological biology of the tumor to enhance its susceptibility to thermal therapy. To this end, a number of opportunities to combine nanoparticles with vascular and immunologically active agents are reviewed. One specific example of preconditioning involves a gold nanoparticle tagged with a vascular targeting agent (i.e., TNF-α). This nanoparticle embodiment demonstrates preconditioning through a dramatic reduction in tumor blood flow and induction of vascular damage, which recruits a strong and sustained inflammatory infiltrate in the tumor. The ability of this nanoparticle preconditioning to enhance subsequent heat or cold thermal therapy in a variety of tumor models is reviewed. Finally, the potential for future clinical imaging to judge the extent of preconditioning and thus the optimal timing and extent of combinatorial thermal therapy is discussed.
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24
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Shafirstein G, Bäumler W, Hennings LJ, Siegel ER, Friedman R, Moreno MA, Webber J, Jackson C, Griffin RJ. Indocyanine green enhanced near-infrared laser treatment of murine mammary carcinoma. Int J Cancer 2011; 130:1208-15. [PMID: 21484791 DOI: 10.1002/ijc.26126] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 03/03/2011] [Accepted: 03/25/2011] [Indexed: 11/06/2022]
Abstract
It is well accepted that near-infrared (NIR) lasers are appropriate to ablate benign lesions and induce irreversible thermal injury in deeply seated blood vessels. At this wavelength, the laser light penetrates deep (3-5 mm) into the skin. However, many researchers have reported noticeable pain, extending from mild to severe, during and immediately after NIR laser treatment. Intravenous administration of an exogenous chromophore [indocyanine green (ICG), dye] can effectively convert NIR laser light into heat. In this approach, the presence of ICG has shown to enhance thermal injury of blood vessels in the treatment of healthy tissues. However, the effectiveness of thermal injury on the regression of cutaneous carcinomas during ICG/NIR laser therapy has not been assessed. The purpose of our study was to evaluate the potential benefit of using ICG/NIR laser therapy to regress superficial carcinoma with thermal injury. Two groups of A/J mice with subcutaneous mammary adenocarcinoma tumors (7-9 mm) were irradiated with a 808-nm NIR laser preceded by tail vein injection of ICG dye or sterile saline. Histological evaluation of the subcutaneous tissue revealed minor thermal damage and necrosis in the laser/saline group and substantial damage (up to 100% necrosis) in the laser/ICG group. The laser/ICG-treated group showed a steady reduction in tumor volume compared to the laser/saline group: 48% by day 5 (p = 0.045) and 69-70% by days 8, 9 and 10 (p values 0.0005 or less). The vascular-targeted ICG-NIR laser therapy appears to have potential for treating superficial tumors.
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Affiliation(s)
- Gal Shafirstein
- Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Winter ND, Murphy RK, Schatz GC, O’Halloran TV. Development and modeling of arsenic-trioxide-loaded thermosensitive liposomes for anticancer drug delivery. J Liposome Res 2011; 21:106-15. [PMID: 20486887 PMCID: PMC3616413 DOI: 10.3109/08982104.2010.483597] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In this article, a novel delivery system for the anticancer drug, arsenic trioxide (ATO), is characterized. The release of ATO from DPPC liposomes with MPPC lysolipid incorporated into the bilayer was measured. Upon heating the liposomes to 37°C, there was a 15-25% release over 24 hours. The ATO release from the DPPC and DPPC:MPPC (5%) systems leveled off after 10 hours at 37°C, whereas the DPPC:MPPC (10%) liposomes continue to release ATO over the 24-hour time span. Upon heating the liposomes rapidly to 42°C, the release rate was substantially increased. The systems containing lysolipids exhibited a very rapid release of a significant amount of arsenic in the first hour. In the first hour, the DPPC:MPPC (5%) liposomes released 40% of the arsenic and the DPPC:MPPC (10%) liposomes released 55% of the arsenic. Arsenic release from pure DPPC liposomes was comparable at 37 and 42°C, indicating that the presence of a lysolipid is necessary for a significant enhancement of the release rate. A coarse-grained molecular dynamics (CGMD) model was used to investigate the enhanced permeability of lysolipid-incorporated liposomes and lipid bilayers. The CG liposomes did not form a gel phase when cooled due to the high curvature; however, permeability was still significantly lower below the liquid-to-gel phase-transition temperature. Simulations of flat DPPC:MPPC bilayers revealed that a peak in the permeability did coincide with the phase transition from the gel to LC state when the lysolipid, MPPC, was present. No pores were observed in the simulations, so it is unlikely this was the permeability-enhancing mechanism.
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Affiliation(s)
- Nicolas D. Winter
- Department of Chemistry, Northwestern University, Evanston, IL 60208
| | - Ryan K.J. Murphy
- Department of Chemistry, Northwestern University, Evanston, IL 60208
| | - George C. Schatz
- Department of Chemistry, Northwestern University, Evanston, IL 60208
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26
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Yu H, Zhu GY, Xu RZ, Niu HZ, Lu Q, Li GZ, Wang ZY, Zhang DS, Gu N, Teng GJ. Arterial embolization hyperthermia using As2O3 nanoparticles in VX2 carcinoma-induced liver tumors. PLoS One 2011; 6:e17926. [PMID: 21448278 PMCID: PMC3063167 DOI: 10.1371/journal.pone.0017926] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Accepted: 02/16/2011] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Combination therapy for arterial embolization hyperthermia (AEH) with arsenic trioxide (As(2)O(3)) nanoparticles (ATONs) is a novel treatment for solid malignancies. This study was performed to evaluate the feasibility and therapeutic effect of AEH with As(2)O(3) nanoparticles in a rabbit liver cancer model. The protocol was approved by our institutional animal use committee. METHODOLOGY/PRINCIPAL FINDINGS In total, 60 VX(2) liver-tumor-bearing rabbits were randomly assigned to five groups (n = 12/group) and received AEH with ATONs (Group 1), hepatic arterial embolization with ATONs (Group 2), lipiodol (Group 3), or saline (Group 4), on day 14 after tumor implantation. Twelve rabbits that received AEH with ATONs were prepared for temperature measurements, and were defined as Group 5. Computed tomography was used to measure the tumors' longest dimension, and evaluation was performed according to the Response Evaluation Criteria in Solid Tumors. Hepatic toxicity, tumor necrosis rate, vascular endothelial growth factor level, and microvessel density were determined. Survival rates were measured using the Kaplan-Meier method. The therapeutic temperature (42.5°C) was obtained in Group 5. Hepatotoxicity reactions occurred but were transient in all groups. Tumor growth was delayed and survival was prolonged in Group 1 (treated with AEH and ATONs). Plasma and tumor vascular endothelial growth factor and microvessel density were significantly inhibited in Group 1, while tumor necrosis rates were markedly enhanced compared with those in the control groups. CONCLUSIONS ATON-based AEH is a safe and effective treatment that can be targeted at liver tumors using the dual effects of hyperthermia and chemotherapy. This therapy can delay tumor growth and noticeably inhibit tumor angiogenesis.
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Affiliation(s)
- Hui Yu
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
| | - Guang-Yu Zhu
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
| | - Rui-Zhi Xu
- Jiangsu Laboratory for Biomaterials and
Devices, State Key Laboratory of BioElectronics, School of Biological Science
and Medical Engineering, Southeast University, Nanjing, China
| | - Huan-Zhang Niu
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
| | - Qin Lu
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
| | - Guo-Zhao Li
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
| | - Zi-Yu Wang
- Department of Pathology and Pathophysiology,
Medical School of Southeast University, Nanjing, China
| | - Dong-Sheng Zhang
- Department of Pathology and Pathophysiology,
Medical School of Southeast University, Nanjing, China
| | - Ning Gu
- Jiangsu Laboratory for Biomaterials and
Devices, State Key Laboratory of BioElectronics, School of Biological Science
and Medical Engineering, Southeast University, Nanjing, China
| | - Gao-Jun Teng
- Jiangsu Key Laboratory of Molecular Imaging
and Functional Imaging, Department of Radiology, Zhong-Da Hospital, Medical
School of Southeast University, Nanjing, China
- * E-mail:
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Dings RPM, Loren ML, Zhang Y, Mikkelson S, Mayo KH, Corry P, Griffin RJ. Tumour thermotolerance, a physiological phenomenon involving vessel normalisation. Int J Hyperthermia 2011; 27:42-52. [PMID: 21204622 DOI: 10.3109/02656736.2010.510495] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The purpose of this study was to delineate the mechanisms by which stromal components of cancer may induce tumour thermotolerance and exploit alterations in stromal and tumour physiology to enhance radiation therapy. The vascular thermoresponse was monitored by daily one-hour 41.5°C heatings in two murine solid tumour models, SCK murine mammary carcinoma and B16F10 melanoma. A transient increase was seen in overall tumour oxygenation for 2-3 days, followed by a progressive decline in tumour pO(2) upon continued daily heatings. Vascular thermotolerance was further studied by treating tumours with different heating strategies, i.e. (1) a single 60 min 41.5°C treatment; (2) two consecutive daily treatments of 41.5°C for 60 min; (3) a single 60 min 43°C treatment or (4) two days of 41.5°C for 60 min followed by treatment with 43°C for 60 min on the third day. Pre-heating tumours with mild temperature hyperthermia induced vascular thermotolerance, which was accompanied by evidence of vessel normalisation, i.e. a decrease in microvessel density and an increase in pericyte coverage. Rational scheduling of fractionated radiation during heat-induced increases in tumour oxygen levels rendered a significantly greater, synergistic, tumour growth inhibition. In vitro clonogenic survival responses of the individual cell types associated (endothelial cells, fibroblasts, pericytes and tumour cells) indicated only a direct cellular thermotolerance in endothelial cells. Overall, this suggests that tumour thermotolerance is a physiological phenomenon mediated through improvement of functional vasculature.
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Affiliation(s)
- Ruud P M Dings
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, MN, USA
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Griffin RJ, Dings RPM, Jamshidi-Parsian A, Song CW. Mild temperature hyperthermia and radiation therapy: role of tumour vascular thermotolerance and relevant physiological factors. Int J Hyperthermia 2010; 26:256-63. [PMID: 20210610 DOI: 10.3109/02656730903453546] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Here we review the significance of changes in vascular thermotolerance on tumour physiology and the effects of multiple clinically relevant mild temperature hyperthermia (MTH) treatments on tumour oxygenation and corresponding radiation response. Thus far vascular thermotolerance referred to the observation of significantly greater blood flow response by the tumour to a second hyperthermia exposure than in response to a single thermal dose, even at temperatures that would normally cause vascular damage. New information suggests that although hyperthermia is a powerful modifier of tumour blood flow and oxygenation, sequencing and frequency are central parameters in the success of MTH enhancement of radiation therapy. We hypothesise that heat treatments every 2 to 3 days combined with traditional or accelerated radiation fractionation may be maximally effective in exploiting the improved perfusion and oxygenation induced by typical thermal doses given in the clinic.
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Affiliation(s)
- Robert J Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72223, USA.
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Horsman MR. Angiogenesis and vascular targeting: Relevance for hyperthermia. Int J Hyperthermia 2009; 24:57-65. [DOI: 10.1080/02656730701829710] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Park SG, Jung JJ, Won HJ, Kang MS, Seo SK, Choi IW, Eun CK, Ahn KJ, Park CW, Lee SW, Lew YS, Bae IJ, Choi IH. Tetra-arsenic oxide (Tetras) enhances radiation sensitivity of solid tumors by anti-vascular effect. Cancer Lett 2009; 277:212-7. [DOI: 10.1016/j.canlet.2008.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Revised: 12/05/2008] [Accepted: 12/08/2008] [Indexed: 11/28/2022]
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Chen Y, Parvez F, Gamble M, Islam T, Ahmed A, Argos M, Graziano JH, Ahsan H. Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Toxicol Appl Pharmacol 2009; 239:184-92. [PMID: 19371619 DOI: 10.1016/j.taap.2009.01.010] [Citation(s) in RCA: 179] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2008] [Revised: 12/05/2008] [Accepted: 01/19/2009] [Indexed: 11/26/2022]
Abstract
The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35-75 million people. Although it is evident that high levels (>300 microg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10-300 microg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominantly at low-to-moderate levels (0.1 to 864 microg/L, mean 99 microg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.
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Affiliation(s)
- Yu Chen
- Departments of Environmental Medicine and Medicine and New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
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Barry SE. Challenges in the development of magnetic particles for therapeutic applications. Int J Hyperthermia 2009; 24:451-66. [PMID: 18608583 DOI: 10.1080/02656730802093679] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Certain iron-based particle formulations have useful magnetic properties that, when combined with low toxicity and desirable pharmacokinetics, encourage their development for therapeutic applications. This mini-review begins with background information on magnetic particle use as MRI contrast agents and the influence of material size on pharmacokinetics and tissue penetration. Therapeutic investigations, including (1) the loading of bioactive materials, (2) the use of stationary, high-gradient (HG) magnetic fields to concentrate magnetic particles in tissues or to separate material bound to the particles from the body, and (3) the application of high power alternating magnetic fields (AMF) to generate heat in magnetic particles for hyperthermic therapeutic applications are then surveyed. Attention is directed mainly to cancer treatment, as selective distribution to tumors is well-suited to particulate approaches and has been a focus of most development efforts. While magnetic particles have been explored for several decades, their use in therapeutic products remains minimal; a discussion of future directions and potential ways to better leverage magnetic properties and to integrate their use into therapeutic regimens is discussed.
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Affiliation(s)
- Stephen E Barry
- Alnis BioSciences, Inc., Research Triangle Park, NC 27709, USA.
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Xiao YF, Wu DD, Liu SX, Chen X, Ren LF. Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice. World J Gastroenterol 2008. [PMID: 18161919 DOI: 10.3748/wjg.13.6498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells. METHODS The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry. RESULTS The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 micromol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls. CONCLUSION Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.
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Affiliation(s)
- Yan-Feng Xiao
- Department of Pediatrics, The Second Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an 710049, Shaanxi Province, China.
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van der Zee J, Vujaskovic Z, Kondo M, Sugahara T. The Kadota Fund International Forum 2004--clinical group consensus. Int J Hyperthermia 2008; 24:111-22. [PMID: 18283588 PMCID: PMC2759185 DOI: 10.1080/02656730801895058] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
The results from experimental studies indicate that hyperthermia is both an effective complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Since the first international hyperthermia conference in 1975, Washington DC, techniques to increase tumour temperature have been developed and tested clinically. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia. The clinical value of hyperthermia in combination with other treatment modalities has been shown by randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, for melanoma and sarcoma. The addition of hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. In spite of these good clinical results, hyperthermia has received little attention. Problems with acceptance concern the limited availability of equipment, the lack of awareness concerning clinical results, and the lack of financial resources. In this paper the most relevant literature describing the clinical effects of hyperthermia is reviewed and discussed, and means to overcome the lack of awareness and use of this modality is described.
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Affiliation(s)
- J van der Zee
- Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
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Abstract
Development of cross-sectional imaging has led to a significant increase in diagnosis of small renal tumors. Nephron-sparing surgery has proven to be effective in the management of these small tumors. Could radiofrequency ablation be as effective in the management of these patients, after showing promising results in a selected group of patients? In this article we discuss the principles of radiofrequency ablation and present results in a selected group of patients. We also outline future perspectives of this noninvasive technique.
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Affiliation(s)
- Adel Abdellaoui
- The Peninsula Medical School, Royal Devon & Exeter NHS Foundation Trust, Radiology Department, Barrack Road, Exeter, EX2 5DW, UK
| | - Anthony F Watkinson
- The Peninsula Medical School, Royal Devon & Exeter NHS Foundation Trust, Radiology Department, Barrack Road, Exeter, EX2 5DW, UK
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Xiao YF, Wu DD, Liu SX, Chen X, Ren LF. Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice. World J Gastroenterol 2007; 13:6498-505. [PMID: 18161919 PMCID: PMC4611288 DOI: 10.3748/wjg.v13.i48.6498] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [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
AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells.
METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry.
RESULTS: The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls.
CONCLUSION: Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.
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Chen Y, Santella RM, Kibriya MG, Wang Q, Kappil M, Verret WJ, Graziano JH, Ahsan H. Association between arsenic exposure from drinking water and plasma levels of soluble cell adhesion molecules. ENVIRONMENTAL HEALTH PERSPECTIVES 2007; 115:1415-20. [PMID: 17938729 PMCID: PMC2022642 DOI: 10.1289/ehp.10277] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2007] [Accepted: 07/17/2007] [Indexed: 05/18/2023]
Abstract
BACKGROUND Epidemiologic studies of cardiovascular disease risk factors and appropriate biomarkers in populations exposed to a wide range of arsenic levels are a public health research priority. OBJECTIVE We investigated the relationship between inorganic arsenic exposure from drinking water and plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), both markers of endothelial dysfunction and vascular inflammation, in an arsenic-exposed population in Araihazar, Bangladesh. METHODS The study participants included 115 individuals with arsenic-related skin lesions participating in a 2 x 2 randomized, placebo-controlled, double-blind trial of vitamin E and selenium supplementation. Arsenic exposure status and plasma levels of sICAM-1 and sVCAM-1 were assessed at baseline and after 6 months of follow-up. RESULTS Baseline well arsenic, a long-term measure of arsenic exposure, was positively associated with baseline levels of both sICAM-1 and sVCAM-1 and with changes in the two markers over time. At baseline, for every 1-mug/L increase in well arsenic there was an increase of 0.10 ng/mL [95% confidence interval (CI), 0.00-0.20] and 0.33 ng/mL (95% CI, 0.15-0.51) in plasma sICAM-1 and sVCAM-1, respectively. Every 1-microg/L increase in well arsenic was associated with a rise of 0.11 ng/mL (95% CI, 0.01-0.22) and 0.17 ng/mL (95% CI, 0.00-0.35) in sICAM-1 and sVCAM-1 from baseline to follow-up, respectively, in spite of recent changes in urinary arsenic as well as vitamin E and selenium supplementation during the study period. CONCLUSIONS The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation that persists over time and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.
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Affiliation(s)
- Yu Chen
- Departments of Environmental Medicine and Medicine, and New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
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Horsman MR, Siemann DW. Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies. Cancer Res 2006; 66:11520-39. [PMID: 17178843 DOI: 10.1158/0008-5472.can-06-2848] [Citation(s) in RCA: 215] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vascular-targeting agent (VTA) have now emerged: those that prevent the angiogenic development of the neovasculature of the tumor and those that specifically damage the already established tumor vascular supply. When used alone neither approach readily leads to tumor control, and so, for VTAs to be most successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy.
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Affiliation(s)
- Michael R Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
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Xiao YF, Liu SX, Wu DD, Chen X, Ren LF. Inhibitory effect of arsenic trioxide on angiogenesis and expression of vascular endothelial growth factor in gastric cancer. World J Gastroenterol 2006; 12:5780-6. [PMID: 17007042 PMCID: PMC4100657 DOI: 10.3748/wjg.v12.i36.5780] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory effect of As2O3 on angiogenesis of tumor and expression of vascular endothelial growth factor (VEGF) in tumor cells in vivo and in vitro.
METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were randomly divided into three groups. As2O3 was injected into the arsenic-treated groups (2.5 mg/kg and 5 mg/kg) and the same volume of saline solution was injected into the control group. Microvessel density (MVD) and expression of VEGF were detected with immunofluorescence laser confocal technology. Further expression of VEGF protein and VEGF mRNA was measured with Western bloting and fluorescence quantitative RT- PCR in SGC-7901 cells treated with As2O3.
RESULTS: In nude mice, after treatment with 5 mg/kg and 2.5 mg/kg As2O3 respectively, about 50% and 30% tumor growth inhibition were observed correspondingly (P < 0.05, P < 0.05). Decrease in MVD appeared in As2O3-treated tumors compared with control group (P < 0.001, P < 0.001). MVD in tumors was significantly lower in 5 mg/kg group than in 2.5 mg/kg group (P < 0.01). The fluorescence intensity levels of VEGF in tumor cells were significantly lowered in the arsenic-treated groups (P < 0.01, P < 0.01). The fluorescence intensity level of VEGF in 5 mg/kg group was lower than that in 2.5 mg/kg group (P < 0.01). In vitro, the expression of VEGF protein decreased in dose- and time-dependent manner after the treatment with As2O3, but in VEGF mRNA no significant difference was found between the control group and the treated groups.
CONCLUSION: As2O3 can inhibit solid tumor growth by inhibiting the formation of new blood vessels. One of the mechanisms is that As2O3 can inhibit VEGF protein expression.
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Affiliation(s)
- Yan-Feng Xiao
- Department of Pediatrics, the Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Huilgol NG. A phase I study to study arsenic trioxide with radiation and hyperthermia in advanced head and neck cancer. Int J Hyperthermia 2006; 22:391-7. [PMID: 16891241 DOI: 10.1080/02656730600722685] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
PURPOSE Arsenic trioxide [ATO] is a pluripotent drug with potentials to have pro-oxidant, angiogenesis inhibitor, flow inhibitor and radiation sensitizer properties. METHODS The present study is a Phase I trial to assess the safety of ATO in advanced or recurrent head and neck cancer treated with radiation and hyperthermia. Patients received ATO at 10, 20 and 30 mg per week a day prior to hyperthermia. RESULTS It was assumed that vascular collapse would be complete by 24 h. Administration of ATO at 20 mg was safe with no toxicity due to ATO. No amplification of toxicities due to radiation or hyperthermia was evident. Patients without prior treatment showed better response. A total of 11 patients were included in this Phase I study. CONCLUSIONS Patients who received 30 mg of ATO weekly showed non-serious acute toxicities. No further escalation of dose was attempted.
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Affiliation(s)
- Nagraj G Huilgol
- Division of Radiation Oncology and Division of Hyperthermic Oncology & Medicine, Dr Balalbhai Nanavati Hospital & MRC, Mumbai, India. /
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Abstract
The most important physiological parameter influencing tissue response to heat is blood flow. At mild hyperthermia temperatures blood perfusion increases in many tumours and this effect is heating time-, temperature- and tumour-dependent. These flow increases can improve tumour oxygenation. When heating is terminated, perfusion and oxygenation commonly recover, although how quickly this occurs appears to be tumour-specific. While these effects are unlikely to have any anti-tumour activity they can be exploited to improve the combination of heat with other therapies. However, since similar physiological effects should occur in normal tissues, such combination therapies must be carefully applied. Heating tumours to higher temperatures typically causes a transient increase in perfusion during heating, followed by vascular collapse which if sufficient will increase tumour necrosis. The speed and degree of vascular collapse is dependent on heating time, temperature and tumour model used. Such vascular collapse generally occurs at temperatures that cause a substantial blood flow increase in certain normal tissues, thus preferential anti-tumour effects can be achieved. The tumour vascular supply can also be exploited to improve the response to heat. Decreasing blood flow, using transient physiological modifiers or longer acting vascular disrupting agents prior to the initiation of heating, can both increase the accumulation of physical heat in the tumour, as well as increase heat sensitivity by changing the tumour micro-environmental parameters, primarily an increase in tumour acidity. Such changes are generally not seen in normal tissues, thus resulting in a therapeutic benefit.
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Affiliation(s)
- Michael R Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus C, Denmark.
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Ning S, Knox SJ. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma. Int J Radiat Oncol Biol Phys 2006; 65:493-8. [PMID: 16563655 DOI: 10.1016/j.ijrobp.2005.12.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2005] [Revised: 12/07/2005] [Accepted: 12/09/2005] [Indexed: 11/17/2022]
Abstract
PURPOSE The primary objective was to optimize the combined treatment regimen using arsenic trioxide (ATO) and fractionated radiotherapy for the treatment of malignant glioma. METHODS AND MATERIALS Nude mice with human glioma xenograft tumors were treated with fractionated local tumor radiation of 250 cGy/fraction/day and 5 mg/kg ATO for 5-10 days. RESULTS Time course experiments demonstrated that maximal tumor growth delay occurred when ATO was administered between 0 and 4 h after radiation. The combination treatment of ATO and radiation synergistically inhibited tumor growth and produced a tumor growth delay time of 13.2 days, compared with 1.4 days and 6.5 days for ATO and radiation alone (p < 0.01), respectively. The use of concurrent therapy of radiation and ATO initially, followed by ATO as maintenance therapy, was superior to the use of preloading with ATO before combined therapy and produced a tumor growth delay time of 22.7 days as compared with 11.7 days for the ATO preloading regimen (p < 0.01). The maintenance dose of ATO after concurrent therapy was effective and important for continued inhibition of tumor growth. CONCLUSIONS The combined use of fractionated radiation and ATO is effective for the treatment of glioma xenograft tumors. ATO was most effective when administered 0-4 h after radiation without pretreatment with ATO. These results have important implications for the optimization of treatment regimen using ATO and fractionated radiotherapy for the treatment of brain tumors.
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Affiliation(s)
- Shoucheng Ning
- Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305-1245, USA
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Hines-Peralta A, Sukhatme V, Regan M, Signoretti S, Liu ZJ, Goldberg SN. Improved tumor destruction with arsenic trioxide and radiofrequency ablation in three animal models. Radiology 2006; 240:82-9. [PMID: 16720872 DOI: 10.1148/radiol.2401050788] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE To assess the extent of tumor blood flow reduction that is achievable with arsenic trioxide (As2O3) and the effect of As2O3 on radiofrequency (RF)-induced coagulation. MATERIALS AND METHODS All animal protocols and experiments were approved by an institutional animal care and use committee before the start of the study. Experiments were conducted in three tumor models: intrarenal VX2 sarcoma in 27 rabbits, RCC 786-0 human renal cell carcinoma in 24 nude mice, and R3230 mammary adenocarcinoma in 40 rats. One dose (0-7.5 mg per kilogram of body weight) of As2O3 was administered (intraperitoneally in rodents, intravenously in rabbits) 1, 6, or 24 hours before standardized RF ablation, which was performed by using a 1-cm active tip, with mean temperatures of 70 degrees C +/- 2 (standard deviation) for 5 minutes in rodents and 90 degrees C +/- 2 for 6 minutes in rabbits. Laser Doppler flowmetry was used to quantify changes in blood flow, which were compared with diameters of induced tumor coagulation. Comparisons between groups were performed by using Student t tests or analysis of variance. The strengths of correlations between As2O3, tumor blood flow, and RF-induced coagulation were assessed by using linear and higher-order regression models and reported as R2 computations. RESULTS Administration of As2O3 significantly (P < .05) reduced blood flow and increased tumor destruction in all tumor models. In VX2 sarcoma tumors, 1 mg/kg As2O3 reduced mean tumor blood flow to 46% +/- 13 of the normal value. The mean resultant coagulation (1.1 cm +/- 0.1) was significantly greater than that achieved with RF ablation alone (0.6 cm +/- 0.1, P < .01). In RCC 786-0 and R3230 tumors, 5 mg/kg As2O3 reduced mean tumor blood flow to 57% +/- 6 and 46% +/- 6 of normal, respectively, increasing mean ablation extent to 0.8 cm +/- 0.1 for both models, compared with those achieved with the control treatment (0.6 cm +/- 0.1 and 0.5 cm +/- 0.1, respectively; P < .05 for both comparisons). Dose studies revealed correlations between drug dose, tumor blood flow, and RF-induced coagulation in all three tumor models (R2 = 0.60-0.79). Maximal RF synergy was observed 1 hour after As2O3 administration. CONCLUSION As2O3 administration represents a transient noninvasive method of reducing tumor blood flow during RF ablation, enabling larger zones of tumor destruction in multiple tumor models.
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Affiliation(s)
- Andrew Hines-Peralta
- Laboratory for Minimally Invasive Tumor Therapy, Department of Radiology, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, WCC 308B, Boston, MA 02215, USA
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Visaria RK, Griffin RJ, Williams BW, Ebbini ES, Paciotti GF, Song CW, Bischof JC. Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-α delivery. Mol Cancer Ther 2006; 5:1014-20. [PMID: 16648573 DOI: 10.1158/1535-7163.mct-05-0381] [Citation(s) in RCA: 165] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF-alpha is systemically toxic, thereby creating a need for its selective tumor delivery. We used a newly developed nanoparticle delivery system consisting of 33-nm polyethylene glycol-coated colloidal gold nanoparticles (PT-cAu-TNF-alpha) with incorporated TNF-alpha payload (several hundred TNF-alpha molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-alpha. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 microg/kg PT-cAu-TNF-alpha alone or followed by local heating at 42.5 degrees C using a water bath for 60 minutes, 4 hours after nanoparticle injection. Increases in tumor growth delay were observed for both PT-cAu-TNF-alpha alone and heat alone, although the most dramatic effect was found in the combination treatment. Tumor blood flow was significantly suppressed 4 hours after an i.v. injection of free TNF-alpha or PT-cAu-TNF-alpha. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF-alpha alone and, in many regions, complete flow inhibition in tumors treated with combination treatment. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 hours after heating, suggesting vascular damage-mediated tumor cell killing. Thermally induced tumor growth delay was enhanced by pretreatment with TNF-alpha-coated gold nanoparticles when given i.v. at the proper dosage and timing.
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Affiliation(s)
- Rachana K Visaria
- Department of Mechanical Engineering, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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Alimoghaddam K, Shariftabrizi A, Tavangar SM, Tavangar M, Sanaat Z, Rostami S, Jahani M, Ghavamzadeh A. Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia. Leuk Lymphoma 2006; 47:81-8. [PMID: 16321832 DOI: 10.1080/10428190500300373] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Arsenic trioxide is now considered the standard agent in treatment of refractory cases of acute promyelocytic leukemia (APL). This drug is also shown to have anti-angiogenesis effect against APL cells in vitro. This study evaluated clinical efficacy and anti-angiogenesis effect of arsenic trioxide in 17 new cases of APL. Arsenic trioxide was given in a dosage of 0.15 mg kg(-1) and remission rate, survival rate, toxicities and effect on vascular density of bone marrow was studied. The bone marrow vascular density was examined using immunohistochemistry for von Willebrand Factor (vWF) and CD31 markers. Bone marrow vascular density was determined by calculating mean vessel number in 3 hot spot, high power microscopic fields. Bone marrow vascular density was reduced as identified by anti-vWF immunohistochemical staining (Mean before treatment = 201.6 mm(-2) +/- 20.4 (SEM), mean after treatment = 109.4 +/- 17.2 (SEM), p < 0.001) and anti-CD31 immunostaining (mean before treatment = 199.17 mm(-2) +/- 21.5 (SEM), mean after treatment = 99.5 mm(-2) +/- 22.1 (SEM), p < 0.05). Treatment efficacy results showed 100% complete remission rate after median of 30 days and 72% survival rate after median 860 days of follow-up. Main toxicities included hyper-leukocytosis, hepatic toxicity and APL differentiation syndrome. The results imply that arsenic trioxide is an effective anti-leukemia and anti-angiogenesis agent in new cases of APL.
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Affiliation(s)
- Kamran Alimoghaddam
- Hematolgy, Oncology and BMT Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Park HJ, Choi EK, Choi J, Ahn KJ, Kim EJ, Ji IM, Kook YH, Ahn SD, Williams B, Griffin R, Boothman DA, Lee CK, Song CW. Heat-induced up-regulation of NAD(P)H:quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin Cancer Res 2006; 11:8866-71. [PMID: 16361576 DOI: 10.1158/1078-0432.ccr-05-0818] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells. EXPERIMENTAL DESIGN Effects of beta-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg beta-lapachone followed by heating the tumors at 42 degrees C for 1 hour every other day for four times. RESULTS Incubation of FSaII tumor cells and A549 tumor cells with beta-lapachone at 37 degrees C reduced clonogenic survival of the cells in dose-dependent and incubation time-dependent manner. NQO1 level in the cancer cells in vitro increased within 1 hour after heating at 42 degrees C for 1 hour and remained elevated for >72 hours. The clonogenic cell death caused by beta-lapachone increased in parallel with the increase in NQO1 levels in heated cells. Heating FSaII tumors in the legs of C3H mice enhanced the effect of i.p.-injected beta-lapachone in suppressing tumor growth. CONCLUSION We observed for the first time that mild heat shock up-regulates NQO1 in tumor cells. The heat-induced up-regulation of NQO1 enhanced the anticancer effects of beta-lapachone in vitro and in vivo.
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Affiliation(s)
- Heon Joo Park
- Radiobiology Laboratory, Department of Therapeutic Radiology/Radiation Oncology, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Brown DB. Concepts, Considerations, and Concerns on the Cutting Edge of Radiofrequency Ablation. J Vasc Interv Radiol 2005; 16:597-613. [PMID: 15872314 DOI: 10.1097/01.rvi.0000156097.63027.7b] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Radiofrequency (RF) ablation is rapidly expanding from a tool to treat isolated hepatic malignancy to a therapy for patients with renal, adrenal, skeletal, breast, lung, and other soft-tissue neoplasms. The purpose of this article is to review the status of RF ablation outside the liver and lung and compare outcomes with current clinical standards when appropriate. The author also reviews how differences in local tissue environments play a role in creation of a thermal lesion and achievement of subsequent clinical success.
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Affiliation(s)
- Daniel B Brown
- Mallinckrodt Institute of Radiology, Washington University Medical Center, St. Louis, Missouri 63110, USA.
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Griffin RJ, Williams BW, Park HJ, Song CW. Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy. Int J Radiat Oncol Biol Phys 2005; 61:1516-22. [PMID: 15817358 DOI: 10.1016/j.ijrobp.2004.12.058] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2004] [Revised: 12/07/2004] [Accepted: 12/16/2004] [Indexed: 12/09/2022]
Abstract
PURPOSE To investigate the effect of arsenic trioxide, Trisenox (TNX), on primary cultures of endothelial cells and tumor tissue under varying pH and pO(2) environments and the effects of combined TNX and radiation therapy on experimental tumors. METHODS AND MATERIALS Human dermal microvascular endothelial cells were cultured in vitro and exposed to TNX under various combinations of aerobic, hypoxic, neutral, or acidic conditions, and levels of activated JNK MAP kinase were assessed by Western blotting. FSaII fibrosarcoma cells grown in the hind limb of female C3H mice were used to study the effect of TNX on tumor blood perfusion and oxygenation. The tumor-growth delay after a single or fractionated irradiation with or without TNX treatment was assessed. RESULTS A single intraperitoneal injection of 8 mg/kg TNX reduced the blood perfusion in FSaII tumors by 53% at 2 hours after injection. To increase the oxygenation of the tumor vasculature during TNX treatment, some animals were allowed to breathe carbogen (95% O(2)/5% CO(2)). Carbogen breathing alone for 2 hours reduced tumor perfusion by 33%. When carbogen breathing was begun immediately after TNX injection, no further reduction occurred in tumor blood perfusion at 2 hours after injection. In vitro, TNX exposure increased activity JNK MAP kinase preferentially in endothelial cells cultured in an acidic or hypoxic environment. In vivo, the median oxygenation in FSaII tumors measured at 3 or 5 days after TNX injection was found to be significantly elevated compared with control tumors. Subsequently, radiation-induced tumor-growth delay was synergistically increased when radiation and TNX injection were fractionated at 3-day or 5-day intervals. CONCLUSIONS Trisenox has novel vascular-damaging properties, preferentially against endothelium in regions of low pH or pO(2), which leads to tumor cell death and enhancement of the response of tumors to radiotherapy.
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Affiliation(s)
- Robert J Griffin
- Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, USA.
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Li X, Ding X, Adrian TE. Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells. Cancer Invest 2004; 22:389-400. [PMID: 15493360 DOI: 10.1081/cnv-200029068] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Arsenic trioxide is valuable for treatment of promyelocytic leukemia, but less attention has been paid to its therapeutic potential for other cancers. In this study, the effects of arsenic trioxide were tested in human pancreatic (AsPC-1), colonic (HT-29), and breast (MCF-7) cancer cells. In all three cancer cell lines, arsenic trioxide inhibited proliferation in a concentration and time-dependent manner, as measured by 3H-methyl thymidine incorporation and cell counting. Coincident with inhibition of growth, arsenic trioxide induced marked morphologic changes, including reduced cytoplasmic volume, membrane blebbing, and nuclear condensation consistent with apoptosis. Propidium iodide DNA staining at 24 hours revealed cell cycle arrest in the G0/G1 phase and an increase in the S phase, while at 72 hr there was G2/M phase arrest with a marked increase in the sub-G0/G1, apoptotic cell population. The DNA fragmentation induced by arsenic trioxide was confirmed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay in all cell lines. Western blot analysis revealed activation of caspase -3, -7, and -9 by arsenic trioxide. Caspase-3 activity was confirmed by demonstrating cleavage of its downstream target, poly ADP-ribose polymerase (PARP). Expression of the antiapoptosis protein, Bcl-2, was time-dependently decreased. In contrast, arsenic trioxide markedly enhanced the expression of the p21 protein, GADD45 and GADD153, in a time-dependent manner. These findings suggest that arsenic trioxide has potential as a therapeutic agent for these cancers.
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Affiliation(s)
- Xinquan Li
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
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Griffin RJ, Monzen H, Williams BW, Park H, Lee SH, Song CW. Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours. Int J Hyperthermia 2004; 19:575-89. [PMID: 14756449 DOI: 10.1080/0265673031000124316] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
It has previously been found that the anti-leukaemia agent Arsenic Trioxide (ATO) causes vascular shutdown in solid tumours and markedly sensitizes tumours to hyperthermia. The present study was designed to evaluate the mechanism of action and dose-dependence of ATO-induced thermosensitization in FSaII and SCK murine tumours. The role of oxidative stress was studied by observing ATO-induced vascular shutdown in vivo and ATO-induced endothelial cell adhesion molecule expression in vitro in the presence or absence of an anti-oxidant. It was found that a dose as low as 2 mg/kg ATO impaired vascular function, as estimated by 86Rb uptake, in the tumour. The degree of tumour growth delay induced by 1 h of hyperthermia at 42.5 degrees C, applied 2 h after ATO injection, was proportional to the dose of ATO administered. In addition, it was found that ATO can directly thermosensitize tumour cells in vitro. The development of massive tissue necrosis in the tumour was observed in the days after treatment, especially with the combination of ATO and heating. ATO-induced adhesion molecule expression in vitro was abolished when the anti-oxidant n-acetyl-cysteine (NAC) was introduced prior to exposure, while the addition of NAC in vivo partially blocked ATO-induced vascular shutdown. These results suggest that the expression of adhesion molecules by the vasculature due to oxidative stress contribute to the ATO-induced selective tumour vascular effects observed and that the clinical use of ATO to increase tumour thermosensitivity via direct cellular and vascular effects appears feasible.
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Affiliation(s)
- R J Griffin
- Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, 420 Delaware St. S.E., MMC 494, Minneapolis, MN 55455, USA.
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