American Association for Cancer Research
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Figure S4 from Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer

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journal contribution
posted on 2023-03-31, 01:24 authored by Jung-Suk Choi, Casey Seol Kim, Anthony Berdis

Chain-termination capabilities of 5-NITP against high fidelity (pol epsilon) and specialized (pol iota) DNA polymerases.

Funding

Department of Defense

the Ohio Third Frontier Foundation, and the Berdis Glioblastoma

History

ARTICLE ABSTRACT

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, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. Cancer Res; 78(4); 1083–96. ©2017 AACR.