Inhibition of nucleoside transporters by tyrosine kinase inhibitors and its effects on chemotherapy efficacy

Abstract

Nucleoside transporters (NTs) are essential for transport of physiologic nucleosides and anticancer nucleoside analogues. There are 7 NTs 5 of which play roles in cellular membrane transport namely human equilibrative nucleoside transporter 1 (hENT1), hENT2, human concentrative nucleoside transporter 1 (hCNT1), hCNT2, and hCNT3. Several studies have demonstrated roles for hENT1 in gemcitabine activity in pancreatic cancer where tumors that have low hENT1 levels have poor response to gemcitabine compared to tumors with high hENT1 levels. Many clinical trial studies with tyrosine kinase inhibitors and a nucleoside analogue backbone have failed or been disappointing. Our group has discovered a possible explanation for the disappointing results of combination regimens consisting of a tyrosine kinase inhibitor (TKI) and a nucleoside analogue. We have found that TKIs have an unappreciated pharmacologic effect in that TKIs are potent NT inhibitors. The NT inhibitory properties may mean that it will be difficult to combine some TKIs with anticancer nucleoside drugs. Careful attention to scheduling the TKI and nucleoside may allow successful combinations of some TKIs and nucleoside anticancer drugs but for some other TKIs due to their long half-lives it may be impossible to successfully schedule them with nucleosides.