Rate of heating as a determinant of hyperthermic cytotoxicity

In Chinese hamster ovary cells and in normal and transformed rat embryonic fibroblasts, survival as a function of time at 42.4 degrees was dependent upon the rate of heating from 37 degrees to 42.4 degrees. Unexpectedly, the untransformed rat fibroblasts were more heat sensitive than were the transformed cells, and the protective effect of slow rates of heating upon survival at 42.4 degrees was also more pronounced in the normal cells than in the transformed cells. In Chinese hamster ovary cells, total cellular cholesterol content and cell volume were found to change significantly with time at 42.4 degrees when cells were heated immediately (37 to 42.4 degrees within 3 min) but did not vary significantly during 6 hr at 42.4 degrees in cells heated from 37 to 42.4 degrees over 3 hr. Chinese hamster ovary cells heated immediately to 42.4 degrees also showed a significant drop in the protein content of the particulate fraction with time at 42.4 degrees. In contrast, cells heated over 3 hr showed a significant increase in the protein content of the particulate fraction with time at 42.4 degrees. These data suggest that, if cells are heated to hyperthermic temperatures over sufficiently long intervals, mechanisms have time to develop which protect the cell membrane against changes associated with cell death in rapidly heated cells. The protective effect of slow rates of heating may partially explain the relative lack of success thus far observed with the use of whole-body hyperthermia in which heating from 37 degrees to 42 degrees often requires 2 to 3 hr.