Thymidine phosphorylase: a two-face Janus in anticancer chemotherapy

Several cytokines and growth factors modulate angiogenesis through a fine tuned paracrine or autocrine mode of action. Among them is plateled-derived endothelial cell growth factor (PD-ECGF), which is highly is expressed in tumors, and is angiogenic by stimulation of endothelial cell migration. Studies have shown that PD-ECGF is identical to the well known enzyme thymidine phosphorylase (TP), which is involved in thymidine metabolism and homeostasis. Interestingly, PD-ECGF plays an angiogenic role as a result of its TP enzyme activity. In light of these findings, PD-ECGF/TP should not be considered a true growth factor, and its PD-ECGF name is now actually a misnomer. Recently, TP activity was thought of as an interesting potential two-face target for controling tumor-dependent angiogenesis. In fact, on one hand, its high levels of expression in tumors compared to non-neoplastic regions, and its broad substrate specificity suggested that TP could be used as an enzymatic tool to locally activate anticancer nucleoside bases or base analogs. On the other hand, its enzyme-dependent angiogenic activity engendered the search for specific inhibitors to reduce TP-dependent angiogenesis. This review will describe TP, its activity, its possible mechanisms of action and its role in angiogenesis. Particular attention will be focused on the design and biological characterization of novel TP inhibitors which recently showed promising anticancer activity.