The cytotoxic effects of 5-fluorouracil (FUra), hyperthermia, and the combination of these treatments were examined in a human T-lymphoblast cell line, CCRF-CEM. Simultaneous exposure of exponentially growing CCRF-CEM cells to hyperthermia (39 and 42°C) and FUra (10, 50, and 100 μ M) for 1 or 2 hr resulted in subadditive or additive cell kill. When CCRF-CEM cells were exposed to these agents in sequence (hyperthermia → FUra and FUra → hyperthermia) for 1 and 2 hr duration additive cell kill was also observed. Enhanced cytotoxic effects were observed when a longer exposure (4 and 8 hr) to FUra (100 μM) followed heat (42°C for 1 and 2 hr). Heat exposure (42°C, 1 and 2 hr) induced a rapid decrease in the synthesis of DNA of CCRF-CEM cells, followed by a rebound increase at 12 hr and a new decrease at 24 hr. Flow cytometry demonstrated an accumulation of cells in the S phase at 12 hr after heat exposure, followed by a marked increase of the G + M population (maximum at 24 hr). The exposure time, and the sequence of administration of hyperthermia and FUra were critical determinants of cytotoxicity in this in vitro system and might constitute important variables of treatment when these two agents are used clinically.
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