Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Abstract

Purpose: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1(hENT1) and human concentrative nucleoside transporter (hCNT) 1and 3 are the major transporters responsible for 2 ¶,2 ¶-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen. Experimental Design: We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1and hCNT3 expression using immunohistochemistry. Results: When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1 high / hCNT3 high expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor. Conclusions: Pancreatic adenocarcinoma patients with a high expression of hENT1and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabinebased adjuvant therapy.Pancreatic head adenocarcinoma has a very poor prognosis.Even after curative surgery, which concerns only 10% to 15% of patients at the time of the diagnosis, 5-year survival is only 10% to 20% and median survival is 20 to 24 months (1, 2). This poor survival rate is attributed to a high rate of local recurrence and development of distant metastases even after complete resection of the tumor (R0 surgery). Several multimodal adjuvant and neoadjuvant therapies have been developed to reduce both local and systemic recurrence of the disease and improve survival. Nevertheless, the value of such adjuvant radiotherapy and/or chemotherapy regimens remains questionable because several trials have failed to draw any firm conclusions. Most of these adjuvant treatments were based on the combination of radiation and 5-fluorouracil (2 -5).Gemcitabine is a 2 ¶,2 ¶-difluoro-2-deoxycytidine analogue that inhibits DNA replication and repair. Gemcitabine monotherapy has clinically important activity in advanced and metastatic pancreatic adenocarcinoma and for which it is now the standard of care (6). In the adjuvant setting, it was enhanced disease-free survival (DFS) and survival compared with surgery alone (7, 8) and significantly increased DFS, but not overall survival (OS), when added to 5-fluorouracil-based chemoradiotherapy in a recent RTOG trial (9).As gemcitabine possesses radiosensitizing prope...

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

“…Gemcitabine is taken up into cells primarily by human concentrative nucleoside transporter 1 and 3 (hCNT1 and hCNT3) and by human equilibrative nucleoside transporter (hENT1) [18]. The expression of these nucleoside transporters is correlated with chemosensitivity and patient survival [19][20][21][22][23]. After being taken into the cells, gemcitabine is activated by deoxycytidine (dCK) [24,25].…”

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

“…5,30 Many studies have shown that the hENT1 but also hCNT3 expression determination can be used as a prognostic marker to provide prospective evaluations for patients receiving gemcitabine-based adjuvant therapy. 6,31,32 In L1210 murine leukaemia cells made resistant to ara-C and cross-resistant to gemcitabine, altered action of dCK can be observed, due to genomic recombination. 27 These results suggest that a partial deletion of the dCK gene observed after selection in the presence of gemcitabine is involved with resistance to this agent both in vitro and in vivo.…”

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

“…Human equilibrative nucleoside transporter-1 (hENT1) and human concentrative nucleoside transporter-3 (hCNT3) both have important roles in the cellular uptake of the nucleoside analog gemcitabine (8). Consistent with this role, PDAC patients with low expression of hENT1 and hCNT3 have significantly worse survival after gemcitabine treatment compared with patients with high hENT1 and hCNT3 expression (9)(10)(11)(12). Although hENT1 expression is currently being evaluated as a biomarker to predict patient response to gemcitabine (13), the molecular mechanisms regulating hENT1 and hCNT3 expression in the PDAC tumor microenvironment are largely unknown.…”