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

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. 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.

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…This phenotypic difference in total polyamine depletion may have more significance in vivo than in vitro, since in the in vivo setting the availability of circulating polyamines may be able to overcome the simple down regulation of ODC exhibited by the small cell lung cancer phenotype. The availability of circulating polyamines apparently caused decreased efficacy in the clinical trial of 2-difluoromethylornithine (DFMO) in small cell lung cancers [1,2]. By contrast, in the nonsmall cell phenotype the increased polyamine catabolism may result in a greater growth inhibitory response in vivo by responding to analogue treatment with both a decrease in biosynthesis and an increase in catabolism.…”

Metabolism and action of amino acid analog anti-cancer agents

“…With prolonged daily dosing, cellular levels of the drug approached 100/t~ with the oral route, while millimolar concentrations were attained after intravenous administration. Abeloff et al (1984) conducted a Phase I trial of DFMO given orally every 6 br for 28 days. Thrombocytopenia was dose-limiting, although nausea, vomiting and audiometric abnormalities were also reported.…”

Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial

“…However, the drug is diffi cult to administer, requiring one slow infusion every 6 h for 14 days (56 infusions in total) because of its short half-life (1·5-5·0 h). 11,12 Effi cacy of a 7-day regimen proved insuffi cient. 13 Despite efl ornithine being available for free, the diffi culty in administering it in resource-poor settings explains why melarsoprol remains the treatment of choice.…”