Hyperthermia treatment (243Β°C) has been shown to be able to (partially) reverse acquired cDDP resistance. However, such heat treatment is difficult to achieve in the clinic. Short pre-treatment at a high temperature (>42"C), immediately before a treatment at a lower temperature (<42"C) can enhance the heat toxicity of the lower temperatures. This "step-down heating schedule" was explored for its possible drug-sensitizing potential in in vitro-cultured cDDP-sensitive and -resistant murine and human tumour cells. A 10-min pre-treatment at 44Β°C enhanced the cytotoxicity of 4 I "C hyperthermia alone. It also enhanced sensitivity to cDDP when given at 37Β°C. However, it did not increase the 4 1Β°C-induced cDDP sensitization. Thus, no correlation was found between heat kill and cDDP sensitization for step-down heating schedules. The observed effects of step-down heating were comparable in sensitive and in resistant cells, so the step-down heating schedule, unlike the 43Β°C treatment, did not lead to a decrease of the cDDP-resistance factor. Yet the total cytotoxicity caused by this treatment protocol was 10-fold more than for cDDP with 41Β°C alone, due to the extra hyperthermic cell killing and the cDDP-sensitizing effect of the pre-treatment. This treatment could have a substantial impact on cDDP efkacy in the clinic even when cDDP resistance has developed.