Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models

Cancer Biology & Therapy
Jessica D SunCharles P Hart

Abstract

Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater or comparable efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an e...Continue Reading

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Citations

Feb 12, 2019·JCO Clinical Cancer Informatics·Sara HamisMark A J Chaplain
Feb 27, 2017·Cancer Chemotherapy and Pharmacology·Richard F RiedelHerbert I Hurwitz
Jul 26, 2017·Antioxidants & Redox Signaling·Yoichi TakakusagiMurali C Krishna
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May 7, 2021·Frontiers in Pharmacology·Yue LiXiao-Feng Li
Aug 17, 2021·Frontiers in Oncology·Yue LiXiao-Feng Li

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Methods Mentioned

BETA
xenograft

Clinical Trials Mentioned

NCT01440088
NCT01746979
NCT02093962

Software Mentioned

GraphPad PRISM

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