Heterogeneity of 5-fluorouracil radiosensitivity modulation in cultured mammalian cell lines

There is ample evidence that 5-fluorouracil (5-FU) improves both local control and survival of a variety of gastrointestinal tumors when added to radiotherapy. However, the modulation of radiosensitivity by 5-FU is incompletely understood and some reports are apparently contradictory. Therefore, we have reevaluated the modulation of radiosensitivity by 5-FU in a variety of mammalian cells. HT-29 and WiDr (human colon adenocarcinoma), DU-145 (human prostate adenocarcinoma), V-79 (Chinese hamster lung fibroblast), and HeLa cell lines were maintained in exponential growth as monolayer cultures. Cell survival following treatment with drug and/or radiation was determined by colony formation assay. Radiation was delivered either alone; midway through a 1 hr exposure to 7-25 micrograms/ml 5-FU (pulse); or following initiation of 0.1-1.5 micrograms/ml 5-FU present throughout the entire incubation for assay of colony forming ability (continuous exposure). These 5-FU levels were selected to approximate those achieved in vivo in humans. The results indicate that mammalian cell lines may vary substantially insofar as modulation of their radiosensitivity by 5-FU is concerned. Radiosensitization, defined by reduction in D0, was observed for continuous exposure only in V-79, WiDr, and HT-29 cell lines, was observed for both pulse exposure and continuous exposure in DU-145, and was not present in HeLa cells. Radioenhancement, defined by reduction in n, was observed in V-79, WiDr, and HT-29 but not in the other cell lines. This effect, characterized by reduction in the shoulder portion of the curve, is naturally accompanied by a decrease of Dq. This indicates that mammalian cell lines may have different responses to radiosensitivity modulation by 5-FU. Though the cell lines may exhibit radiosensitivity by either alterations in the slope or shoulder of the cell survival curve, the mechanisms responsible for both the heterogeneity as well as the radiosensitization itself are completely unknown at this time. Insight into the mechanisms for both the heterogeneity and the radiosensitization will be important areas for further investigation.