Effect of Step-Down Heating on the Cytotoxicity of Adriamycin, Bleomycin, and c/s-Diamminedichloroplatinum1

The cytotoxicity of a number of anticancer drugs can be potentiated by mild hyperthermia. Since the cytotoxicity of lowhyperthermic temperatures in the range of 39-43° can be poten tiated by using a step-down heating (SDH) sequence (short times at >45° followed by longer times at lower temperatures), we investigated the combined effects of SDH (specifically 45°, 10 min, followed by time at 41.5°) and three chemotherapeutic drugs known to be more toxic at elevated temperatures. In agreement with previous observations with Chinese ham ster cells, we found that cultured RIF tumor cells showed an increased rate of cell killing at 41.5°when the low-temperature heat treatment was preceded by an acute heat shock of 10 min, 45°.Similarly, RIF cells showed enhanced cytotoxicity of Adria mycin, bleomycin, and cisplatin at 41.5° over that at 37°, as reported previously for hamster cells. When SDH and drug exposures were combined, the rate of cell killing was greater than that observed with the drugs at a constant 41.5°. SDH alone reduced the D0 on the 41.5°survival curve from approxi mately 500 min to 100 min after 10 min at 45°. Adriamycin cytotoxicity (0.3 /«g/ml)at 41.5° was characterized by a D0 of approximately 160 min for treatment times of 1 to 4 hr; with SDH, this was reduced to 52 min. Similarly, bleomycin (5 fig/m\) and cisplatin (0.5 ^g/ml) showed a decrease in D0 by factors of 1.4 (68 to 48 min) and 2 (25.2 to 13.5 min), respectively, with the SDH sequence when compared with drug toxicity at 41.5° alone. However, the sensitization to cisplatin was the same when 10 min at 45° was followed by drug exposure at 37°, or at 41.5°. The results indicate that Adriamycin and bleomycin, but not cisplatin, cytotoxicity was increased by SDH over that achiev able with 41.5°alone. Possible clinical implications are discussed briefly.