| Nucleoside transporters are crucial for the cellular transport of a wide variety of both natural and chemotherapeutic nucleoside analogs. We recently discovered that a number of commonly used protein kinase inhibitors blocked the cellular uptake of nucleosides and nucleoside analogs into tumor cells (1,2). The sum of these studies suggested that nucleoside transporters were unexpected targets for direct inhibition by these compounds. In addition we observed that other kinase inhibitors influenced nucleoside uptake through effects consistent with inhibition of kinase-dependent expression of these proteins. Specifically these studies suggested that nucleoside transporter expression was enhanced by activation of the BCR-ABL, Src or EGF receptor tyrosine kinases. In addition, other studies have implicated activation of the MAP kinases (JNK) in regulating the expression of these transporters in response to cell stress. Thus the objectives of this project are to determine the kinase-dependent signals that regulate nucleoside transport expression as well as to investigate the pharmacological effects of inhibiting nucleoside uptake in both normal or tumor cells. |