A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer

Abstract

3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

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

“…It is clear, however, from our experience and that of others [18,19], that 3-AP can induce methemoglobinemia even in the absence of G6PD deficiency. In a recent report in which 3-AP was combined with gemcitabine, 5 of 18 patients treated at the 105 mg/m 2 dose level of 3-AP (given as a 2 to 4 h infusion), had documented hypoxia in association with the 3-AP infusion [18]. Three of these patients had met-Hg levels checked and had modest elevation in levels (10.8% to 12%) [18].…”

“…In a recent report in which 3-AP was combined with gemcitabine, 5 of 18 patients treated at the 105 mg/m 2 dose level of 3-AP (given as a 2 to 4 h infusion), had documented hypoxia in association with the 3-AP infusion [18]. Three of these patients had met-Hg levels checked and had modest elevation in levels (10.8% to 12%) [18]. We observed dose-limiting methemoglobinemia at the 100 mg/m 2 dose level of 3-AP, and transient reversible methemoglobinemia in the majority of patients studied at the 75 mg/m 2 dose level.…”

Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine

“…In our patient with unrecognized G6PD deficiency, methylene blue increased hemolysis without contributing to methemoglobin reduction. Our patient's methemoglobinemia gradually improved as the Triapine was metabolized (T 1/2 ¼ 1-2 hr) [4]. Notably, his methemoglobin level had already fallen from 35% after the second Triapine treatment to 10.3% 24 hr later, prior to treatment with methylene blue.…”

“…Triapine has previously been associated with mild methemoglobinemia [4], likely related to oxidative effects [5] that were exacerbated in our patient G6PD deficiency. Methemoglobin is formed when hemoglobin iron is oxidized and is no longer able to bind oxygen.…”

“…Recently, an experimental ribonucleotide reductase inhibitor [3], 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; TriapineÒ; Vion Pharmaceuticals Inc., New Haven, CT) has been associated with mild methemoglobinemia [4]. We report herein an extreme example of this side effect, treated by methylene blue, which resulted in massive hemolysis because of concomitant unrecognized G6PD deficiency.…”