Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer.

Abstract

Nucleoside-derived anticancer agents must be transported across the plasma membrane as a preliminary step to their conversion into active drugs. Hence, modulation of a specific nucleoside transporter may affect bioavailability and contribute significantly to sensitizing tumor cells to these anticancer agents. We have generated and functionally characterized a new recombinant adenovirus (Ad-hENT1) that has allowed us to overexpress the equilibrative nucleoside transporter hENT1 and to analyze its effects in human pancreatic tumor cells. Overexpression of hENT1 is associated with changes in cell cycle profile, in a variable manner depending on the particular cell type, thus suggesting a metabolic link between hENT1-mediated transport processes and the enzymatic machinery responsible for intracellular nucleoside metabolism. When assayed in vivo in a human pancreatic adenocarcinoma xenograft, intratumoral Ad-hENT1 injection improved the therapeutic response to gemcitabine. In summary, hENT1 overexpression is associated with alterations in nucleoside enzymatic machinery and cell cycle progression in cultured cells and enhances gemcitabine action in vivo.

• Authors: Sandra Pérez-Torras, José García-Manteiga, Elena Mercadé, F Javier Casado, Neus Carbó, Marçal Pastor-Anglada, Adela Mazo
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 76 Issue 3 Pg. 322-9 (Aug 01 2008) ISSN: 1873-2968 [Electronic] England
• PMID: 18589402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Equilibrative Nucleoside Transporter 1
• Recombinant Fusion Proteins
• SLC29A1 protein, human
• Deoxycytidine
• Uridine
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Adenoviridae (genetics)
• Animals
• Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Equilibrative Nucleoside Transporter 1 (biosynthesis, genetics)
• Female
• Genetic Vectors
• Humans
• Injections, Intralesional
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Biosynthesis (drug effects, genetics)
• Recombinant Fusion Proteins (administration & dosage)
• Reverse Transcriptase Polymerase Chain Reaction
• Uridine (metabolism)
• Xenograft Model Antitumor Assays
• Gemcitabine