Clinical Development of 4-Hydroperoxyifosfamide

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DESCRIPTION (provided by applicant): The objective of the proposed research is to synthesize 4-hydroperoxyifosfamide (HOO-IFOS) in sufficient quantity for evaluation in vivo against a human osteosarcoma xenograft and additional tumor xenografts of breast, lung (small cell and non-small cell) and ovary cancers. A cyclophosphamide-resistant human melanoma xenograft will also be used in order to determine the efficacy of this pre-activated form of the clinical antitumor drug ifosfamide (IFOS) in comparison with IFOS, cyclophosphamide (CPA) and 4-hydroperoxycyclophosphamide (4-HC) as a guide to possible further development of HOO-IFOS as a clinical anticancer agent. Plasma levels of chloroacetaldehyde, a metabolite of IFOS implicated as the causative agent in its neurotoxicity, and acrolein, the metabolite of IFOS and CPA that causes dose-limiting hemorrhagic cystitis, generated by HOO-IFOS vs. IFOS will be measured as an indication of comparative neurotoxic or hemorrhagic cystitic potential, resp. Possible clinical advantages of HOO-IFOS in comparison to IFOS or CPA are (1) elimination of variation in active drug administered to patients, (2) reduction or elimination of toxicities associated with IFOS or CPA and (3) possible reduction in CPA-related resistance. PROPOSED COMMERCIAL APPLICATIONS: It is possible that HOO-IFOS could become a superior clinical drug to CPA or IFOS for treating certain tumor types now treated with these two drus because of comparable/superior activity but with reduced toxicities.