Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer

Allyson J. Ocean, Paul Christos, Joseph A. Sparano, Dan Matulich, Andreas Kaubish, Abby Siegel, Max Sung, Maureen M. Ward, Nancy Hamel, Igor Espinoza-Delgado, Yun Yen, Maureen E. Lane

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)379-388
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number2
DOIs
StatePublished - Aug 2011

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gemcitabine
Biliary Tract Neoplasms
Ribonucleotide Reductases
Liver
Biliary Tract
Adenocarcinoma
Tumors
Hydroxyurea
Fine Needle Biopsy
Neutropenia
Tumor Cell Line
Thrombocytopenia
Needles
Fatigue
3-aminopyridine
Anemia
Urinary Bladder
Cells
Fatigue of materials
Confidence Intervals

Keywords

  • 3-aminopyridine-2- Carboxaldehydethiosemicarbazone
  • Biliary tract cancer
  • Gemcitabine
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer. / Ocean, Allyson J.; Christos, Paul; Sparano, Joseph A.; Matulich, Dan; Kaubish, Andreas; Siegel, Abby; Sung, Max; Ward, Maureen M.; Hamel, Nancy; Espinoza-Delgado, Igor; Yen, Yun; Lane, Maureen E.

In: Cancer Chemotherapy and Pharmacology, Vol. 68, No. 2, 08.2011, p. 379-388.

Research output: Contribution to journalArticle

Ocean, Allyson J. ; Christos, Paul ; Sparano, Joseph A. ; Matulich, Dan ; Kaubish, Andreas ; Siegel, Abby ; Sung, Max ; Ward, Maureen M. ; Hamel, Nancy ; Espinoza-Delgado, Igor ; Yen, Yun ; Lane, Maureen E. / Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 68, No. 2. pp. 379-388.
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abstract = "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.",
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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.

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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.

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