3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Leukemia

Triapine, a potent inhibitor of ribonucleotide reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1-5 and 15-19 or 1-5 and 8-12 of a 4-week cycle. When administered twice a day on days 1-5 and 8-12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2-5.5 microM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Infusions, Intravenous; Leukemia; Male; Maximum Tolerated Dose; Middle Aged; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones

Topics: Enzyme Inhibitors; Humans; Leukemia; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones