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Cisplatin and hyperthermia treatment of a C3H mammary carcinoma in vivo. Importance of sequence, interval, drug dose, and temperature.

The effect of combining cisplatin and hyperthermia was investigated in a C3H mammary carcinoma in vivo, using a regrowth delay assay. Cisplatin (6 mg/kg) was given i.p. at intervals ranging from 24 h before to 24 h after a 43.5 degrees C/60 min treatment. A supra-additive effect was obtained by giving cisplatin 15 min before heat, whereas an additive effect was obtained at all other intervals. The importance of cisplatin dose and heating temperature were investigated by giving variable cisplatin doses (2-8 mg/kg) 4 h or 15 min before a 60 min heating at temperatures in the range 40.5-43.5 degrees C. Linear relationships between length of regrowth delay and cisplatin dose were obtained both for cisplatin alone and for the combined treatment. The effect of the combined treatment could therefore be quantitated by a ratio (ER) between the slopes of dose-response curves. The ER values for cisplatin give 4 h before a 60 min heating at 42.5 or 43.5 degrees C were not significantly different from 1 (p greater than 0.5). In contrast, significant ER values were obtained above 40.5 degrees C (p less than 0.05) for cisplatin given 15 min before heat. The data demonstrates the possibility of achieving chemosensitization at clinically relevant temperatures.