TY - JOUR
T1 - Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer
AU - Ocean, Allyson J.
AU - Christos, Paul
AU - Sparano, Joseph A.
AU - Matulich, Dan
AU - Kaubish, Andreas
AU - Siegel, Abby
AU - Sung, Max
AU - Ward, Maureen M.
AU - Hamel, Nancy
AU - Espinoza-Delgado, Igor
AU - Yen, Yun
AU - Lane, Maureen E.
N1 - Funding Information:
This study was performed by the New York Cancer Consortium (www.newyorkcancerconsortium.org), and was supported by a contract from the National Institute of Health, National Cancer Institute (N01-CM-62204 [PI: Joseph A. Sparano]) and NIH Subcontract 24XS07, P6254 (PI: Maureen E. Lane).
PY - 2011/8
Y1 - 2011/8
N2 - Background: 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma. Methods: Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m2 on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m2 in patients with normal liver function (stratum A) or 80 mg/m2 if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B. Results: Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3-4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT-PCR, suggesting RR inhibition. Conclusions: Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.
AB - Background: 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma. Methods: Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m2 on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m2 in patients with normal liver function (stratum A) or 80 mg/m2 if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B. Results: Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3-4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT-PCR, suggesting RR inhibition. Conclusions: Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.
KW - 3-aminopyridine-2- Carboxaldehydethiosemicarbazone
KW - Biliary tract cancer
KW - Gemcitabine
KW - Ribonucleotide reductase
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U2 - 10.1007/s00280-010-1481-z
DO - 10.1007/s00280-010-1481-z
M3 - Article
C2 - 20981545
AN - SCOPUS:79960914223
SN - 0344-5704
VL - 68
SP - 379
EP - 388
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -