Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion

Wadler, Scott; Makower, Della; Clairmont, Caroline; Lambert, Paula; Fehn, Karen; Sznol, Mario

doi:10.1200/jco.2004.07.158

Cited by 127 publications

(101 citation statements)

References 29 publications

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“…The 3-AP starting dose and schedule were chosen based on prior phase I single agent experience with this drug in solid tumors and hematologic malignancies [7,[10][11][12]. In these trials, a 96-h continuous infusion caused more renal and hepatic toxicity compared with a 2-h infusion given daily for 5 days and repeated every 2 to 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

et al. 2008

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SummaryPurpose-This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine.Experimental design-Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m 2 /day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h.Results-In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m 2 ). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/m 2 dose level. Objective evidence of clinical activity was observed in four patients.Conclusions-The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m 2 /day of 3-AP on days 2-5 given prior to cytarabine administered at a dose of 1,000 mg/m 2 /day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.

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Section: Methodsmentioning

confidence: 99%

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

et al. 2008

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“…7 The best studied HCT to date is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), also referred to as Triapine, which has already been examined in several clinical phase I and II trials. 8,9,10 Triapine was found to be safe and effective against hematologic malignancies, e.g. leukemia.…”

Section: Introductionmentioning

confidence: 99%

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

et al. 2014

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The nickel(II), copper(II) and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H 2 L 1 ) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazonehave been synthesized and characterized by elemental analysis, one-and two-dimensional 1 H and 13 C NMR spectroscopy, CD, UV−vis and ESI mass spectrometry. Compounds 13, 6 and 7 have been also studied by single crystal X-ray diffraction. Magnetic properties and solid state high-field EPR spectra of 2 over the range 50420 GHz were investigated. The complex formation processes of L-Pro-FTSC with nickel(II) and zinc(II) have been studied in aqueous solution due to the excellent water solubility of the complexes via pH-potentiometry, UV−vis and 1 H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.3

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“…RR contains a tyrosine free radical required for enzymatic reduction of ribonucleotides and 3-AP inactivates RR by neutralizing this free radical. Phase I trials with single-agent 3-AP showed solid tumor activity, including one of two patients with pancreatic cancer who experienced stable disease of three months duration and a 33% decrease in CA 19-9 [11][12][13]. Pharmacokinetics and tolerability data determined that a feasible regimen for phase II testing was 96 mg/m 2 /day as a 2-hour infusion for four days every two weeks.…”

Section: Introductionmentioning

confidence: 99%

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

et al. 2008

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Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion

Abstract: The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.

Cited by 127 publications

References 29 publications

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

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