Biological rationale for hyperthermia in cancer treatment (II).

Hyperthermia (HT) has gained a great interest in the past two decades. The nature of hyperthermia-induced cell lethality is quite different from that of radiation-induced killing. The G1-phase of the cell cycle is the most resistant to HT while S-phase cells are quite sensitive. In addition to heat-induced cytotoxicity, HT sensitizes cells to low LET ionizing radiation. The mechanism of heat cytotoxicity is distinct from that of ionizing radiation. Unlike the response to ionizing radiation, heat cytotoxicity is influenced by thermotolerance, low pH and nutritional deprivation, but is independent of acute hypoxia. Also, blood flow influences the heating characteristics of a tumor relative to normal tissue, and vascular collapse may occur after heating. Thermotolerance is a nonheritable resistance to HT induced by exposure to heat and other cytotoxic agents. Thermotolerance develops within 2-3 h during exposure to temperatures less than 43 degrees C. Cells exposed for a brief period to temperatures higher than 43 degrees C are sensitized to exposure to temperatures below 43 degrees C. This is called "stepdown heating, SDH". SDH results from the inhibition of thermotolerance development by exposure to the high temperature. Cells are sensitized to HT damage by acutely lowering pH, and thermotolerance development is reduced at low pH. Reduced pH also enhances thermoradiosensitization. Since much of a tumor population is at low pH, and these tumor cells are very likely to be hypoxic and radioresistant, this offers one of the strongest reasons for combining HT with radiation therapy in the treatment of human tumors. The neovasculature in tumors does not respond to increased temperatures as do blood vessels in normal tissues, and these differences in blood flow may lead to selective tumor heating. HT dramatically enhances the cytotoxicity of the electron affinic radiosensitizers in hypoxic cells. HT sensitizes the cell to many cytotoxic agents and even converts some drugs that are innocuous to highly toxic. HT chemosensitization may occur by an increased reaction rate, increased permeability, or decreased repair. The most promising chemosensitization by HT would seem to be with alkylating agents and cis-platinum since they are enhanced at all elevated temperatures.