Pentoxifylline inhibits gene-specific repair of UV-induced DNA damage in hamster cells

Abstract

We have studied the effect of pentoxifylline (PTX) on DNA repair after ultraviolet radiation (UV) in Chinese hamster ovary cells (CHO). DNA repair of cyclobutane pyrimidine dimers (CPDs) was measured in the dihydrofolate reductase (DHFR) gene and in a downstream nontranscribed genomic region. Pentoxifylline (1 mM) inhibited the repair of CPDs in the hamster DHFR gene by 32% after 8 hr of repair incubation. This decrease in repair of CPDs in the DHFR gene correlated with an enhancement of UV-induced cell killing by PTX. The UV doses required for 37% survival after incubation with 0 and 1 mM PTX were 6.2 J/m2 and 2.9 J/m2, respectively. This represents twofold more UV-induced cytotoxicity in irradiated cells in the presence of PTX. We then evaluated the effect of PTX on RNA transcription and cell cycle kinetics. Incubation of UV-irradiated CHO cells with PTX had no effect on the transcription of the DHFR gene. PTX did not produce a significant effect on cell cycle progression during 8 hr after UV-irradiation. However, by 24 hr after irradiation, incubation with PTX induced a distinct block in early S-phase. We conclude that PTX sensitizes CHO cells to UV-irradiation, perhaps because it inhibits DNA repair of active genes. Radiat Oncol Invest 1996;4:115–121. © 1996 Wiley-Liss, Inc.