SBIR-STTR Award

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.

Thesaurus Terms:
antineoplastic, drug design /synthesis /production, drug screening /evaluation, ifosfamide, osteosarcoma breast neoplasm, cyclophosphamide, lung neoplasm, melanoma, ovary neoplasm athymic mouse

4-Hydroperoxyifosfamide (HOO-IFOS) is a stable, pre-activated form (peroxide) of 4-HO-IFOS, the initial metabolite of Ifosfamide (IFOS). Under physiological conditions HOO-IFOS under goes spontaneously ring opening and conversion to isophosphoramide mustard (IPM), the active cytotoxic metabolite of IFOS. The objective of the proposed research is to synthesize 4-hydroperoxyifosfamide (HOO-IFOS) in sufficient quantity to document and validate purity and stability. A lyophilized product will be prepared at The University of Iowa, Pharmaceutical Services under GLP/GMP guidelines for clinical use in patients with advanced cancer. GC/MS and HPLC assays will be validated for quantification of bulk and pharmaceutical grade drug. Toxicology studies using a 3-day dosing regime in mice and dogs will be conducted at a GLP facility using the final product. An assay to monitor plasma HOO-IFOS PK and acrolein/chloroacetaldehyde levels in dogs receiving HOO- IFOS will be finalized. An IND package will be prepared after all the above has been finalized and submitted to the FDA. In summary - HOO-IFOS had improved anticancer activities vs. human glioblastoma and breast cancer xenografts and CPA-resistant leukemia murine models. The goal of the SBIR application will be to develop a new pro-drug, 4-hydroperoxyifosfamide (HOO-IFOS) that will generate in vivo - isophosphoramide mustard (IPM) - with reduced formation of associated toxic - chloroacetaldehyde and acrolein - by-products, normally produced during IFOS