title: Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.
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 equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Sun
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Ahluwalia
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Ferraro
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Don
authors.initials: D
authors.lastname: Jung
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Matteucci
authors.affiliation: a Threshold Pharmaceuticals , South San Francisco , CA , USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010752:Phosphoramide Mustards / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D007069:Ifosfamide
keywords: Evofosfamide; hypoxia; hypoxia-activated prodrug; ifosfamide; non-small cell lung cancer; xenograft
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