Perturbation of thymidine kinase regulation: a novel chemotherapeutic approach

The design of compounds which disrupt the regulation of key enzymes is a new strategy for drug development. 5'-AdThd, which can antagonize the feedback inhibition that normally regulates thymidine kinase, is representative of this novel class of agents. The ability of 5'-AdThd to deinhibit thymidine kinase markedly increases the capacity of some cells to phosphorylate thymidine and IdUrd and, thereby, enhance their cytotoxicity. This effect is evident in three human bladder cancer cell lines, but not in normal human urothelial cells. Thus, 5'-AdThd may be able to increase the therapeutic selectivity of IdUrd. Intracellular dTTP pools are critically involved in mediating the effects of 5'-AdThd, but differences in these pools from cell type of cell type may not account for the selective stimulation of IdUrd uptake produced in the cancer cells.