Urano M, Ling C C
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Int J Hyperthermia. 2002 Jul-Aug;18(4):307-15. doi: 10.1080/02656730210123534.
It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5 degrees C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5 degrees C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T(0) (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37 degrees C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T(0) at 37 degrees C to the T(0) at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.
业已证实，热疗可增强某些化疗药物的细胞毒性。这已引发了多种热化疗的临床试验，尽管许多问题仍未得到解答。人们研究了各种药物在高温下对具有不同组织病理学的动物肿瘤的影响。这些研究表明，烷化剂在适度升温时对所有肿瘤最为有效。顺铂对所有肿瘤也有效，但其在41.5摄氏度时的有效性低于烷化剂。为了定量研究这些发现，通过集落形成试验研究了烷化剂美法仑和新型铂化合物奥沙利铂在37 - 44.5摄氏度时的热增强程度。每种药物的剂量保持恒定，细胞存活率作为治疗时间的函数来确定。在所有测试温度下，细胞存活曲线与治疗时间呈指数关系，且T(0)（存活从1降至0.37的时间）随温度升高而降低。这些结果表明，这些药物在37摄氏度时以恒定速率产生细胞毒性作用，且该速率随温度升高而加快。这表明热可加速细胞毒性化学反应，导致显著的热增强。热增强比（TER，37摄氏度时的T(0)与升温时的T(0)之比）随温度升高而增加。在实验室测试的药物中，美法仑在适度升温时的活化能最大，而奥沙利铂的活化能约为美法仑活化能的一半。这表明美法仑或烷化剂细胞毒性的热增强可能最大。文中还讨论了细胞毒性热增强的潜在机制。
