Enhanced cell killing by bleomycin and 43 degrees hyperthermia and the inhibition of recovery from potentially lethal damage

Abstract

The effect of hyperthermia on bleomycin (BLEO) toxicity and repair was studied in "unfed" monolayer cultures of Chinese hamster cells. Synergy of toxicities was observed with simultaneous exposure to BLEO and 43 degrees. For example, when cells were exposed for 1 hr to BLEO (40 mug/ml) at 43 degrees, survival was reduced to 4 X 10(-5); separately, hyperthermia and 37 degrees BLEO exposure each resulted in a survival of 20%. Heating at 43 degrees prior to drug exposure at 37 degrees also produced substantial sensitization, indicating that the primary sensitizing effect involved cell damage rather than an increased rate of drug action; 41 degrees produced only modest cell sensitization to BLEO and the effect was not retained in cells heated prior to drug exposure. No increase in [14C]BLEO uptake was observed at 43 degrees over than at 37 degrees, and thus the increased cytotoxicity was not correlated with a gross change in cell permeability to BLEO, although increased drug availability to particular sensitive targets could not be ruled out. Studies of the repair kinetics after different 43 degrees BLEO protocols demonstrated that most of the cells sustaining potentially lethal damage rapidly recovered. However, 43 degrees hyperthermia inhibited this recovery and, with increasing durations of 43 degrees exposure, the fixation of potentially lethal damage was enhanced. Because of the substantial repair of BLEO damage observed in vivo, the possible usefulness of hyperthermia as an adjunct to BLEO therapy is discussed.