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End-joining Deficiency and Radiosensitization Induced by Gemcitabine

Department of Pulmonary Diseases, University Hospital, 9713 GZ Groningen [J. W. G. v. P., H. J. M. G.]; Department of Internal Oncology, University Hospital Vrije Universiteit, 1007 MB Amsterdam [K. S., G. J. P.]; and Department of Radiation and Stress Cell Biology, University of Groningen, 9713 AV Groningen, the Netherlands [H. H. K.]

The mechanism of radiosensitization by gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is not exactly known. We investigated the possible role of inhibition of the repair of DNA double-strand breaks by dFdC by measuring the extent of radiosensitization in different cell lines deficient and proficient in components of nonhomologous end-joining and in the parental cell lines. Different cell lines were incubated with 0.5 and 5 µM dFdC for 4 h. Cells deficient in DNA-dependent protein-kinase catalytic subunit (V3) showed sensitization similar to that of wild-type cells (AA8) and complemented cells (V3+YAC). Ku80-deficient cells (xrs5 and xrs6) showed even more radiosensitization by dFdC as compared with wild-type CHO-K1. However, Ku80-complemented cell lines (xrs5+huKu80 and xrs6+haKu80) did not show radiosensitization. The differences in dFdC-mediated radiosensitization were not attributable to different changes in deoxynucleotide triphosphate levels and cell cycle distribution. We conclude that a functional nonhomologous end-joining pathway is not required for dFdC-mediated radiosensitization.

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