MLH1 deficiency enhances radiosensitization with 5-fluorodeoxyuridine by increasing DNA mismatches.

ABSTRACT: The antitumor drug 5-fluoro-2'-deoxyuridine (FdUrd) also sensitizes tumor cells to ionizing radiation in vitro and in vivo. Although radiosensitization with FdUrd requires dTTP depletion and S-phase arrest, the exact mechanism by which these events produce radiosensitization remains unknown. We hypothesized that the depletion of dTTP produces DNA mismatches that, if not repaired before irradiation, would result in radiosensitization. We evaluated this hypothesis in mismatch repair (MMR)-deficient HCT116 0-1 cells that lack the expression of the required MMR protein MLH1 (inactive MLH1), and in MMR-proficient (wild-type MLH1) HCT116 1-2 cells. Although HCT116 0-1 cells were less sensitive to FdUrd (IC(50) = 3.5 microM) versus HCT116 1-2 cells (IC(50) = 0.75 microM), when irradiation followe

SUBMITTER: Flanagan SA 

PROVIDER: S-EPMC2615187 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature