The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors.

Cancer Chemotherapy and Pharmacology
Brian S ChoiKyle Holen

Abstract

3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms. The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC. Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung canc...Continue Reading

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Citations

Mar 20, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Peter H O'Donnell, Walter M Stadler
Apr 11, 2013·Parasitology Research·Mônica Caroline Oliveira CamposLeonor Laura Leon
Nov 2, 2012·Pharmaceuticals·Sanath R WijerathnaChris G Dealwis
Jan 18, 2018·Antioxidants & Redox Signaling·Petra HeffeterChristian R Kowol
May 23, 2012·International Journal of Urology : Official Journal of the Japanese Urological Association·Xi LinFeng-Shuo Jin

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