Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central Nervous System

Abstract

Background: 4-Hydropeoxyifosfamide (HOOI) is a hydroperoxy derivative of ifosfamide that was developed as an anticancer agent that can penetrate the blood-brain barrier (BBB), which can be potentially useful in the management of brain tumors. Methods:A novel synthetic scheme for HOOI is presented and verified. HOOI and an HOOI L-lysine salt were prepared and mice implanted intracranially (IC) and in the mammary fat pad with human U251 glioblastoma, D54 glioblastoma, and MX-1 breast tumor xenografts and treated with HOOI IP once daily for 1-5 days. The animals were monitored for responses, increased long-term survival (ILS) and long-term survival (LTS). Mice, rats, and dogs received single IV doses of HOOI in a wide range of concentrations and results are compared and presented herein.Results: HOOI has been synthesized as per a new route in 67% yield. The drug is stable when frozen in the absence of moisture; however, as a lysine salt the drug is stable in solution and as a lyophilized product. HOOI produced complete responses with improved long-term survival against IC implanted U251 glioblastoma, D54 glioblastoma, and MX-1 breast tumor xenografts in mice. The drug was superior to 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHC-PEN) and BCNU vs. IC implanted tumor models. The HOOI lysine salt demonstrated equal activity to that of HOOI alone. Over all, the drug was well tolerated. Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 39 mg/m 2 with a clearance of 11 L/h +/− 2.75 and a T 1/2α 15 min and T ½β 5.30 h for a 70 kg human patient. The presented toxicity data plus strong antineuro-oncology activity supports DM-CHOC-PEN's proposed use as a treatment for CNS malignancies. The drug is being prepared for Phase I trial studies in the US-IND pending.