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Effect of Step-Down Heating on the Cytotoxicity of Adriamycin, Bleomycin, and cis-Diamminedichloroplatinum¹

Veterans Administration Medical Center [T. S. H., A. J. M., T. P. M.], and Departments of Internal Medicine [T. S. H., K. J. H., T. P. M.], Physiology/Biophysics [K. J. H., W. A. N., A. J. M.], and Radiology [W. A. N., A. J. M.], University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

The cytotoxicity of a number of anticancer drugs can be potentiated by mild hyperthermia. Since the cytotoxicity of low-hyperthermic temperatures in the range of 39–43° can be potentiated 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 hamster 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 Adriamycin, 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 approximately 500 min to 100 min after 10 min at 45°. Adriamycin cytotoxicity (0.3 µg/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 µg/ml) and cisplatin (0.5 µg/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 achievable with 41.5° alone. Possible clinical implications are discussed briefly.

¹ Supported in part by Veterans Administration Merit Review funding and USPHS Grants CA 32154 and CA 35689.

² Present address: Division of Radiation Oncology, Department of Radiology, Stanford University, Stanford, CA 94305. To whom requests for reprints should be addressed.

Received 10/24/83. Accepted 2/ 8/84.