Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer.

Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2'-deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2'-deoxyriboside triphosphate, creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA.