Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis.

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Abstract
.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. The maximally tolerated dose of oral DFMO administered every 6 h for 28 days to patients with advanced solid tumors of lymphomas was determined. 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 4 patients who had no prior chemotherapy had no decrease in the platelet count. The steady-state levels of DFMO achieved at the highest dose (3 g/m2) were 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 6 h is recommended for phase II studies in patients previously treated with cytotoxic drugs.