Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.
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/m(2) 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/m(2) in patients with normal liver function (stratum A) or 80 mg/m(2) 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.
Ocean
Allyson J
AJ
New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.
Christos
Paul
P
Sparano
Joseph A
JA
Matulich
Dan
D
Kaubish
Andreas
A
Siegel
Abby
A
Sung
Max
M
Ward
Maureen M
MM
Hamel
Nancy
N
Espinoza-Delgado
Igor
I
Yen
Yun
Y
Lane
Maureen E
ME
D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D044963:Biopsy, Fine-Needle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D048550:Hepatic Insufficiency / Q000150:complications; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011725:Pyridines; D012333:RNA, Messenger; D013882:Thiosemicarbazones; D003841:Deoxycytidine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine