STEP-DOWN HEATING ENHANCES THE CYTOTOXICITY OF HUMAN TUMOR-NECROSIS-FACTOR ON MURINE AND HUMAN TUMOR-CELL LINES IN-VITRO

The response of tumour necrosis factor (TNF)-sensitive murine L929 cel ls to TNF was enhanced similar to 1000-fold after step-down heating (S DH) for 30 min at a sensitizing temperature (ST) of 43 degrees C and a subsequent 24 h incubation at a test temperature (TT) of 40.5 degrees C, compared to continuous treatment at 37 degrees C. The TNF-resistan t phenotype of murine EMT-6 mammary adenocarcinoma cells could be over come by 24 h heating at a TT of 40.5 degrees C, and their sensitivity to TNF could be further increased by preheating at the ST for up to 60 min. The response of TNF-sensitive HCT-15 human colon adenocarcinoma cells was somewhat similar to that of L929 cells except that there was a similar to 2.5 log increase in TNF-sensitivity due solely to heatin g at 40.5 degrees C. The response of TNF-resistant DLD-1 human colon a denocarcinoma cells was similar to that of EMT-6 cells. In contrast, t hree normal cell lines demonstrated greater resistance to any TNF/SDH treatment examined. Our results suggest that SDH may overcome the resi stance or enhance the response of tumour cells to TNF while minimizing cytotoxic effects on normal cells.