Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidinephosphorylase

The angiogenic factor platelet-derived endothelial cell growth factor/thymi dine phosphorylase (PD-ECGF/ITP) is expressed at higher levels in a wide va riety of solid tumors compared to adjacent normal tissues. Patients with PD -ECGF/TP-positive colon and esophageal tumors have a poorer prognosis than those with negative tumors. The expression of PD-ECGF/TP is a prognostic fa ctor independent of microvessel density suggesting that TP has effects on t umor progression independent of its angiogenic activity. Evidence that hypo xia and apoptosis affect tumor growth prompted us to determine whether incr eased expression of PD-ECGF/TP prevents apoptosis induced by hypoxia. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF /TP, 2-deoxy-D-ribose and thymine partially prevented hypoxia-induced apopt osis. The ability of 1 mu M 2-deoxy-D-ribose in combination with the same c oncentration of thymine to prevent hypoxia-induced apoptosis was similar to that of the overexpressed TP in KB cells. A concentration of 1 mu M 2-deox y-L-ribose abrogated the effects of these degradation products of thymidine . These findings suggested that TP can confer resistance to apoptosis induc ed by hypoxia and the degradation products of thymidine are involved in thi s resistance. Expression of PD-ECGF/TP may play an important role in the pr ogression of solid tumors, and inhibitors of TP and analogs of the degradat ion products of thymidine may suppress the growth of tumors by promoting ap optosis. (C) 1998 Academic Press.