The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma.
OBJECTIVE
Gemcitabine monotherapy is the standard palliative chemotherapy for pancreatic adenocarcinoma. Gemcitabine requires plasma membrane nucleoside transporter proteins to efficiently enter cells and exert it cytotoxicity. In vitro studies have demonstrated that deficiency of human equilibrative nucleoside transporter 1 (hENT1), the most widely abundant and distributed nucleoside transporter in human cells, confers resistance to gemcitabine toxicity, but the distribution and abundance of nucleoside transporters in normal and malignant pancreatic tissue is unknown.


METHODS
We studied tumor blocks from normal pancreas and 21 Alberta patients with gemcitabine-treated pancreatic cancer. Immunohistochemistry on the formalin-fixed, paraffin-embedded tissues was performed with specific hENT1 and human Concentrative Nucleoside Transporter 3 monoclonal antibodies and scored by a pathologist blinded to clinical outcomes.


RESULTS
hENT1 was detected in normal Langerhan cells and lymphocytes but not in normal glandular elements. Patients in whom all adenocarcinoma cells had detectable hENT1 had significantly longer median survivals from gemcitabine initiation than those for whom hENT1 was absent in a proportion (10 to 100%) of adenocarcinoma cells (median survival, 13 versus 4 months, P = 0.01). Immunohistochemistry for human Concentrative Nucleoside Transporter 3 revealed moderate to high-intensity staining in all adenocarcinoma tissue samples.


CONCLUSIONS
Patients with pancreatic adenocarcinoma with uniformly detectable hENT1 immunostaining have a significantly longer survival after gemcitabine chemotherapy than tumors without detectable hENT1. Immunohistochemistry for hENT1 shows promise as a molecular predictive assay to appropriately select patients for palliative gemcitabine chemotherapy but requires formal validation in prospective, randomized trials.
Spratlin
Jennifer
J
University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
Sangha
Randeep
R
Glubrecht
Darryl
D
Dabbagh
Laith
L
Young
James D
JD
Dumontet
Charles
C
Cass
Carol
C
Lai
Raymond
R
Mackey
John R
JR
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine