Evaluation of Thymidine Phosphorylase Inhibitors in Glioblastoma and Their Capacity for Temozolomide Potentiation

A number of studies have shown high levels of thymidine phosphorylase (TP) expression in glioblastoma (GBM), with trace or undetectable TP levels in normal developed brain tissue. TP catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate, maintaining nucleoside homeostasis for efficient DNA replication and cell division. The TP-mediated catabolism of thymidine is responsible for multiple protumor processes and can support angiogenesis, glycation of proteins, and alternative metabolism. In this study, we examined the effect of TP inhibition in GBM using the known nanomolar TP inhibitors 5-chloro-6-[1-(2'-iminopyrrolidin-1'-yl)methyl]uracil (TPI) and the analogous 6-[(2'-aminoimidazol-1'-yl)methyl]uracils. Although these TP inhibitors did not demonstrate any appreciable cytotoxicity in GBM cell lines as single agents, they did enhance the cytotoxicity of temozolomide (TMZ). This pontetiated action of TMZ by TP inhibition may be due to limiting the availability of thymine for DNA repair and replication. These studies support that TP inhibitors could be used as chemosensitizing agents in GBM to improve the efficacy of TMZ.