The clinical use of hyperthermia in combination with radiation or chemotherapeutic agents has been demonstrated to be effective against cancer for a variety of tumor types. A potential problem in its application is that thermotolerance, a transient resistance to heat killing, has been shown to develop during prolonged, continuous exposures of tumors at temperatures below 42.5 degrees celsius which is commonly used. Thermotolerance may also develop in tumors when hyperthermic treatments are fractionated at intervals less than 72 hours. A fundamental understanding of the molecular and cellular mechanisms of the development of thermotolerance will be needed for the improvement of the clinical application of hyperthermia and to exploit it to optimal advantage. There appear to be two distinct types of transient thermal resistance. One of them is partially dependent on protein synthesis, particularly the family of heat shock proteins (HSP). Another type which is independent of protein synthesis is not well studied or understood. The objective of this proposed study is to elucidate the mechanism of the development of protein synthesis-independent transient thermal resistance. We will investigate three alternative pathways which may involve in this type of thermal resistance. We propose that transient thermal resistance is mediated by eliminating thermolabile peptides, protection from protein denaturation, or enhancement of repair efficiency. These studies will hopefully provide a better understanding of mechanisms of development of transient thermal resistance and stress management in general as well as enable us to improve the efficacy of clinical hyperthermia in a clinical cancer treatment setting.