THYMIDINE PHOSPHORYLASE MODERATES THYMIDINE-DEPENDENT RESCUE AFTER EXPOSURE TO THE THYMIDYLATE SYNTHASE INHIBITOR ZD1694 (TOMUDEX) IN-VITRO

The inhibition of de novo thymidine (dThd) synthesis by the novel fola te-based thymidylate synthase (TS) inhibitor ZD1694 (Tomudex) can achi eve tumor cell-specific cytotoxicity in vivo. However, nucleosides in the surrounding microenvironment of tumors may be used by the salvage pathway to regenerate any depleted pools, thus providing an efficient mechanism through which to circumvent the ZD1694-dependent toxicity. A nabolism of dThd to dTMP by dThd kinase (TK) is the first committed st ep in the dThd salvage pathway. However, dThd phosphorylase (dThdPase) can compete with TK by catalyzing the reversible phosphorolytic cleav age of dThd to thymine and deoxyribose I-phosphate and rendering the s alvaged dThd metabolically unavailable. Both TK and dThdPase are up-re gulated in some tumors, and their relative importance is not fully def ined. We have studied the influence of dThdPase expression on the capa city of exogenous dThd to reverse ZD1694-dependent growth inhibition a nd have shown that both intra-and extracellular dThdPase activity can effectively moderate dThd-rescue. This suggests that tumor levels of d ThdPase may be an important factor in the outcome of ZD1694 therapy.