Increased cytotoxicity of low-dose, long-duration exposure to 5-fluorouracil of V-79 cells with hyperthermia.

We examined the cytotoxic effects of combined low dose and long exposure to 5-fluorouracil (5-FU) and hyperthermia on Chinese hamster V-79 cells with reference to timing and sequence of administration. The survival rate following hyperthermia at 42 degrees C for 2 h alone was 95.4%, and that after exposure to 1.0 micrograms/ml/5-FU alone for 48 hours, 94.2%. With respect to the combination of 5-FU and heat, the survival rate of cells exposed to hyperthermia at 42 degrees C for 2 h followed by 1.0 micrograms/ml 5-FU treatment for 48 h followed by hyperthermia led to a survival rate of 10%. Flow cytometric analysis of V-79 cells after exposure to 1.0 micrograms/ml 5-FU for 48 h revealed an accumulation of cells in the S-phase; the percentage of S-phase exponential growing cells was 65% and the plateau phase was 38%. The former were more sensitive to heat than the latter cells according to the MTT assay. V-79 cells pretreated with 5-FU were more sensitive to hyperthermia than were those not pretreated with 5-FU. Therefore, when 5-FU plus heat is to be used to treat a patient with a malignancy, the sequence of 5-FU followed by hyperthermia may be more effective than the reverse.