Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model.
Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D003072:Cognition Disorders / Q000139:chemically induced*; D003244:Consciousness Disorders / Q000139:chemically induced* / Q000188:drug therapy; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy*; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D010830:Physostigmine / Q000627:therapeutic use; D013064:Speech Disorders / Q000139:chemically induced
D000970:Antineoplastic Agents; D006827:Hydantoins; D009588:Nitrogen Mustard Compounds; D010830:Physostigmine; C015511:spiromustine