Step down heating and melphalan: cytotoxic interactions and clinical implications

Step down heating from 41.8 degrees C (10, 15 and 20 min) to 40.5 degrees C (55, 50 and 45 min respectively) was studied in vitro in L929 sarcoma cells in the presence and absence of increasing doses of melphalan. Results for heat killing alone demonstrated that step down heating for 20 min (but not 10 or 15 min) at 41.8 degrees C was equivalent to 41.8 degrees C x 65 min. Heat enhancement of melphalan, however, was observed at 10, 15 and 20 min with thermal enhancement ratios of 8.3, 10.3 and 8.5 respectively (p < or = 0.01), consistent with the enhancement of 41.8 degrees C x 65 min. The relevance of these data to hyperthermic limb perfusions for the treatment of malignant melanoma and sarcoma are discussed.