Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer
| Autor: | W. Steve Ammons, Damien Ferraro, Jingli Wang, Qian Liu, Yan Wang, Charles P. Hart, Dharmendra Ahluwalia, Jian-Xin Duan, John G. Curd, Mark D. Matteucci, Jessica D Sun |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty DNA damage Antineoplastic Agents Mice SCID Biology Mice chemistry.chemical_compound Cell Line Tumor medicine Bystander effect Animals Humans Pimonidazole Prodrugs Evofosfamide Neovascularization Pathologic Tumor hypoxia Cancer Neoplasms Experimental Prodrug medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Cell Hypoxia Oncology chemistry Nitroimidazoles Cancer research Female Phosphoramide Mustards |
| Zdroj: | Clinical Cancer Research. 18:758-770 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-11-1980 |
| Popis: | Purpose: Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models. Experimental Design: Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by γH2AX immunohistochemistry. Results: TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumor-bearing animals breathing 95% O2 exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O2 exhibited enhanced TH-302 efficacy, both compared with air (21% O2) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by γH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a “bystander effect.” Conclusions: The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues. Clin Cancer Res; 18(3); 758–70. ©2011 AACR. |
| Databáze: | OpenAIRE |
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