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Time-dose relationships for 5-fluorouracil cytotoxicity against human epithelial cancer cells in vitro.

Abstract The purpose of this study was to ascertain time-dose relationships for 5-fluorouracil (5-FUra) cytotoxicity against a variety of human epithelial cancer cells in vitro . Three human colon adenocarcinomas (HT-29/SP-1, LoVo/SP-1, Colo 205), two human cervix carcinomas (HeLa, Me-180-VC1), and one human ovary carcinoma (Ovary 2008-VC1) were examined for their clonogenic capacity following various 5-FUra treatment regimens. The 5-FUra regimens ranged from traditional bolusequivalent concentrations (25 to 500 µg/ml) administered for 1 hr (approximate complete serum clearance time) to clinically achievable infusion concentrations (1.0 µg/ml) administered for 72 hr. The time-dose relationships obtained in this manner indicated that: ( a ) relatively high drug concentrations are required for pulse exposures of 5-FUra to be cytocidal against these human cancer cells and that human cell sensitivity even within the same tissue type can vary significantly under these conditions (range of doses lethal to 50% of the cells, 30 to 120 µg/ml); ( b ) tremendous reductions in cell survival can be produced by a very restricted 5-FUra dose range (1 to 4 µg/ml) if exposure times are extended beyond the cell cycle time. The data suggest that human cell sensitivities to 5-FUra exhibit less variation under prolonged infusion regimens (72-hr range of doses lethal to 50% of the cells, 0.5 to 1.0 µg/ml). The 5-FUra time-dose relationships are discussed with regard to patient serum clearance times for bolus versus infusion 5-FUra clinical regimens. Our most important conclusions are that the 5-FUra concentrations necessary to achieve a level of cell toxicity for these same lines for exposures of 1 full hr are probably not clinically achievable by bolus 5-FUra therapy administrations. These experiments suggest that, when 5-FUra is administered at lower doses for longer time periods, it is more effective in producing direct cytotoxic effects in human tumor cells than when administered at higher doses for shorter times.