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Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies.

Abstract
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.
AuthorsIvana Gojo, Michael L Tidwell, Jacqueline Greer, Naoko Takebe, Karen Seiter, Mary F Pochron, Bonny Johnson, Mario Sznol, Judith E Karp
JournalLeukemia research (Leuk Res) Vol. 31 Issue 9 Pg. 1165-73 (Sep 2007) ISSN: 0145-2126 [Print] England
PMID17324462 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Pyridines
  • Thiosemicarbazones
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • Ribonucleotide Reductases
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (administration & dosage, pharmacokinetics)
  • Female
  • Humans
  • Infusions, Intravenous
  • Leukemia (blood, drug therapy)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Pyridines (administration & dosage, pharmacokinetics)
  • Ribonucleotide Reductases (antagonists & inhibitors)
  • Thiosemicarbazones (administration & dosage, pharmacokinetics)

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