The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells.

Abstract

Although 5-fluoro-2'-deoxyuridine (FdUrd) has been combined with hyperfractionated radiation therapy in clinical trials, the optimal method of delivering radiation therapy is not yet known. To determine the importance of the time interval between fractions on the survival of tumor cells exposed to FdUrd, we studied the effect of FdUrd on sublethal damage repair in HT29 human colon cancer cells in culture. Cells were exposed to clinically achievable concentrations of FdUrd (10-100 nM) for 14 hr followed by either single dose (8-12 Gy) or split dose (4-6 Gy x 2) external cobalt irradiation. The interval between radiation fractions was varied from 0.5 to 6 hr. FdUrd impaired sublethal damage repair in a dose dependent fashion. FdUrd had no effect on the induction of DNA double strand breaks (DSB's), but significantly reduced the rate of the repair of DNA DSB's. Exposure to 100 nM FdUrd decreased intracellular TTP pools but elevated dATP pools. These findings suggest that FdUrd may decrease sublethal damage repair by perturbing nucleotide triphosphate pools, which leads to a decrease in the ability of the cell to repair DNA DSB's. Furthermore, they suggest that hyperfractionated irradiation will be superior to once daily treatment when combined with regional delivery of FdUrd.