Engin K
Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107-5097.
Neoplasma. 1994;41(5):277-83.
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.
在过去二十年中，热疗（HT）引起了极大的关注。热疗诱导细胞致死的性质与辐射诱导杀伤的性质有很大不同。细胞周期的G1期对热疗最具抗性，而S期细胞则相当敏感。除了热诱导的细胞毒性外，热疗还使细胞对低线性能量传递电离辐射敏感。热细胞毒性的机制与电离辐射不同。与对电离辐射的反应不同，热细胞毒性受热耐受性、低pH值和营养剥夺的影响，但与急性缺氧无关。此外，血流影响肿瘤相对于正常组织的加热特性，加热后可能发生血管塌陷。热耐受性是对热和其他细胞毒性剂暴露诱导的热疗的非遗传性抗性。在暴露于低于43摄氏度的温度期间，热耐受性在2-3小时内形成。短暂暴露于高于43摄氏度温度的细胞对低于43摄氏度的温度暴露敏感。这被称为“逐步降温加热，SDH”。SDH是由于暴露于高温抑制了热耐受性的形成。通过急性降低pH值，细胞对热疗损伤敏感，并且在低pH值下热耐受性的形成减少。降低的pH值也增强了热放射增敏作用。由于许多肿瘤群体处于低pH值，并且这些肿瘤细胞很可能是缺氧和放射抗性的，这为在人类肿瘤治疗中将热疗与放射治疗相结合提供了最有力的理由之一。肿瘤中的新生血管不像正常组织中的血管那样对温度升高作出反应，并且这些血流差异可能导致肿瘤选择性加热。热疗显著增强了缺氧细胞中亲电子放射增敏剂的细胞毒性。热疗使细胞对许多细胞毒性剂敏感，甚至将一些无毒药物转化为高毒性药物。热疗化学增敏作用可能通过反应速率增加、通透性增加或修复减少而发生。热疗最有前景的化学增敏作用似乎是与烷基化剂和顺铂，因为它们在所有升高的温度下都增强。
