Clinical Development of 4-Hydroperoxyifosfamide

描述（由申请人提供）：拟议研究的目的是合成足够数量的4-氢过氧异磷酰胺（HOO-IFOS），以在体内评估对人类骨肉瘤异种移植和其他乳腺癌、肺癌（小细胞和非小细胞）和卵巢癌的肿瘤异种移植。还将使用一种对环磷酰胺耐药的人类黑色素瘤异种移植物，以确定这种预激活形式的临床抗肿瘤药物IFOS （IFOS）与IFOS、环磷酰胺（CPA）和4-氢过氧环磷酰胺（4-HC）的疗效，作为进一步开发HOO-IFOS作为临床抗癌药物的指导。氯乙醛（IFOS的代谢物，是其神经毒性的致病因子）和丙烯醛（IFOS和CPA的代谢物，导致剂量限制性出血性膀胱炎）的血浆水平将被测量，分别作为比较神经毒性或出血性膀胱潜能的指示。与IFOS或CPA相比，HOO-IFOS可能的临床优势是：(1)消除给患者的活性药物变化，(2)减少或消除与IFOS或CPA相关的毒性，(3)可能减少与CPA相关的耐药性。

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.