title: Phase I studies on chlorozotocin.
abstract: A phase I investigation of chlorozotocin, a new-water soluble chloroethylnitrosourea, was undertaken to define its pharmacologic effects in man. Forty-three patients received single intravenous doses ranging from 5 to 175 mg/m2 every 6 wk. No signs of toxicity were observed at doses of under 120 mg/m2, but thrombocytopenia occurred at higher doses. The thrombocytopenic nadir appeared to be dose-dependent and occurred 4 wk after treatment. Platelet transfusions were required in 2 patients who had previously received intensive chemotherapy. No significant leukopenia occurred. A mild reversible and delayed elevation of hepatic transaminases was found in 25% of courses of 120 mg/m2 or more. No renal toxicity was observed and gastrointestinal toxicity was mild. Investigation of clinical pharmacology revealed a rapid triphasic plasma clearance with initial t1/2S of 3, 15, and 30 min. The concentration of N-nitroso intact drug at 1 hr was 10% of the initial peak level. Renal excretion accounted for half of the dose. No significant concentration of N-nitroso intact or radiolabeled drug was detected in the cerebrospinal fluid of 2 patients in whom it was examined. There were objective signs of therapeutic activity in 5 patients, 3 of whom had melanoma. Based on these studies, the recommended dose for phase II investigation of chlorozotocin is 120 mg/m2 every 6 wk.
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002648:Child; D002986:Clinical Trials as Topic; D004341:Drug Evaluation; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D007700:Kinetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013311:Streptozocin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C007028:chlorozotocin; D013311:Streptozocin