Clinical Development of 4-Hydroperoxyifosfamide

描述(申请人提供)：拟议研究的目标是合成足够数量的4-羟基过氧异环磷酰胺(HoO-IFOS)，用于体内评估对人骨肉瘤移植瘤和其他乳腺癌、肺癌(小细胞和非小细胞)和卵巢癌的移植瘤。还将使用对环磷酰胺具有抗药性的人黑色素瘤异种移植瘤，以确定这种预激活形式的临床抗肿瘤药物异环磷酰胺(IFOS)与IFOS、环磷酰胺(CPA)和4-羟基过氧环磷酰胺(4-HC)的比较效果，作为进一步开发HoO-IFOS作为临床抗癌剂的指导。血浆中IFOS的代谢物氯乙醛和丙烯醛的水平将分别作为比较神经毒性或出血性膀胱炎的指标，前者是IFOS的代谢物，被认为是导致其神经毒性的原因；后者是IFOS和CPA的代谢物，导致剂量限制的出血性膀胱炎。与IFOS或CPA相比，HoO-IFOS可能的临床优势是：(1)给患者使用的活性药物不同，(2)减少或消除与IFOS或CPA相关的毒性，以及(3)可能减少CPA相关的耐药性。 建议的商业应用： HOO-IFOS有可能成为治疗某些肿瘤类型的优于CPA或IFOS的临床药物，因为这两种药物的活性相当/优越，但毒性较低。

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.