Heat-induced cell death and radiosensitization: molecular mechanisms.

Although several lines of evidence suggest that the cellular membrane plays a role in heat-induced cell death, a basic question remains unanswered. Namely, how does membrane damage lead to reproductive death which is traditionally thought to reflect DNA damage? Recent results suggest that membrane damage in the absence of heat can cause an increase in chromatin protein content similar to that induced by hyperthermia. The increased protein content in chromatin could cause structural alterations that lead to inhibition of enzyme-mediated DNA function. These alterations appear to play a major role in heat-induced radiosensitization by inhibiting the repair of X-ray-induced DNA strand breaks and thymine damage. The correlation between cell killing by heat alone and the increase in chromatin content imply that structural alterations in chromatin are part of the killing mechanism. Recently, heat-induced DNA damage has been observed. Therefore, the molecular mechanism by which hyperthermia kills cells could involve DNA damage resulting from alterations in chromatin structure.