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TH-302 (evofosfamide) is a hypoxia-activated prodrug composed of a 2-nitroimidazole moiety linked to bromo-isophosphoramide mustard (Br-IPM), a DNA cross-linking agent. Under hypoxic conditions commonly found in solid tumors, the prodrug is reduced and releases Br-IPM, which alkylates DNA and induces cytotoxicity specifically in low oxygen environments. Doxorubicin is an anthracycline chemotherapeutic that intercalates DNA and inhibits topoisomerase II, leading to cell death primarily in normoxic tumor regions. The combination of TH-302 with doxorubicin targets both hypoxic and normoxic compartments within tumors, aiming for broader antitumor activity without increased systemic toxicity. This combination has been investigated primarily for advanced or metastatic soft tissue sarcoma and osteosarcoma[1][2][3][4][5][6].
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