Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity.

Abstract

Salvage of preformed nucleosides requires transport across the plasma membrane by sodium-dependent (concentrative) and sodium-independent (equilibrative) mechanisms. These transport systems are also the route of cellular uptake for nucleoside analogues, including gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analogue used in the treatment of pancreatic cancer. To determine whether gemcitabine cytotoxicity is influenced by the equilibrative-sensitive nucleoside transporter (es-NT), basal levels of the es-NT were quantified in three human pancreatic cancer cell lines (PANC-1, HS-766T, and PK-8) and one human bladder cancer cell line (MGH-U1) by flow cytometric analysis, and the results were compared with gemcitabine cytotoxicity assessed by clonogenic assay. To determine whether the salvage pathway of DNA synthesis can be up-regulated by inhibiting de novo DNA synthesis, combination experiments were carried out using the thymidylate synthase (TS) inhibitors 5-fluorouracil or raltitrexed with gemcitabine in a concurrent and sequential fashion. No relationship between basal es-NT and gemcitabine cytotoxicity was demonstrated. For two pancreatic cell lines, sequence-dependent effects of the combination of TS inhibitors and gemcitabine were seen with maximum effect when the TS inhibitors preceded gemcitabine. This was also associated with a significant increase in es-NT levels caused by the TS inhibitors. Thus, modulation of the es-NT by pretreatment with TS inhibitors may have the potential to improve the therapeutic benefit of gemcitabine.

• Authors: D R Rauchwerger, P S Firby, D W Hedley, M J Moore
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 21 Pg. 6075-9 (Nov 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 11085530 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Carrier Proteins
• Equilibrative Nucleoside Transport Proteins
• Fluoresceins
• Fluorescent Dyes
• Purine Nucleosides
• Quinazolines
• Thiophenes
• Deoxycytidine
• 5-(SAENTA-x8)fluorescein
• raltitrexed
• Fluorouracil
• Gemcitabine

Topics

• Antimetabolites, Antineoplastic (pharmacokinetics, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (toxicity)
• Carrier Proteins (metabolism)
• Cell Survival (drug effects)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• Equilibrative Nucleoside Transport Proteins
• Flow Cytometry
• Fluoresceins (metabolism)
• Fluorescent Dyes (metabolism)
• Fluorouracil (administration & dosage, toxicity)
• Humans
• Inhibitory Concentration 50
• Pancreatic Neoplasms (drug therapy, metabolism)
• Purine Nucleosides (metabolism)
• Quinazolines (administration & dosage, toxicity)
• Thiophenes (administration & dosage, toxicity)
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms (drug therapy, metabolism)
• Gemcitabine