Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis.
alpha-Difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase, blocks polyamine biosynthesis and has antitumor effects in animal tumor models as well as in athymic mice implanted with human small cell carcinoma. This study was designed to determine the maximally tolerated dose of oral DFMO administered every six hours for 28 days to patients with advanced solid tumors or lymphomas. DFMO levels were measured using an ion exchange chromatographic assay and pharmacokinetic studies were performed in patients treated at each dose level. Twenty-two patients received 24 courses of DFMO. The drug was generally well tolerated. Thrombocytopenia was the dose-limiting toxicity and gastrointestinal side effects were also seen. Thrombocytopenia developed in 11 of 16 patients who had received prior chemotherapy but the four patients who had no prior chemotherapy had no decrease in the platelet count. The steady state level of DFMO achieved at the highest dose (3 g/m2) were found to be within the range needed for inhibition of ornithine decarboxylase in cell-culture systems as well as for the inhibitory activity against various human tumors in vitro. A DFMO dose of 2.25 g/m2 every six hours is recommended for phase II studies in patients previously treated with cytotoxic drugs.
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D004341:Drug Evaluation; D000518:Eflornithine; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009952:Ornithine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism
D000970:Antineoplastic Agents; D011073:Polyamines; D009952:Ornithine; D000518:Eflornithine