Da Silva V F, Feeley M, Raaphorst G P
University of Ottawa, Ottawa Civic Hospital, Canada.
J Neurooncol. 1991 Aug;11(1):37-41. doi: 10.1007/BF00166995.
Experimental evidence indicating potentiation of the cytotoxic effect of drugs at high temperatures suggests that the utilization of drug-heat combinations for gliomas of the brain might be therapeutically useful. Hyperthermia may increase the cytotoxicity of a particular drug in areas of low drug concentration/time and in cell populations resistant to the drug. We report in vitro experiments with a BCNU resistant, U-373MG, and a BCNU sensitive, U-87MG, human derived glioma cell lines under hyperthermic conditions. Temperatures equal or above 42 degrees C potentiate BCNU cell kill in both lines. The thermo-sensitizer lidocaine increases thermal cell kill but only minimally with concentrations corresponding to therapeutic plasma lidocaine levels. Within our experimental conditions, the best strategy to overcome BCNU resistance involved a combination of heat, BCNU and cis-DDP. BCNU resistant cells have no cross resistance to cis-DDP and the combination of BCNU and cis-DDP is synergistic. At modest hyperthermic conditions (42 degrees C) 99.4% BCNU resistant cells are killed by a combination of BCNU and cis-DDP at drug concentrations identical to plasma concentrations after standard IV doses. Clinical protocols using heat and drug may need to incorporate two or more drugs for optimal effects.
实验证据表明，高温下药物的细胞毒性作用会增强，这表明药物与热联合应用于脑胶质瘤可能具有治疗作用。热疗可能会增加特定药物在低药物浓度/时间区域以及对该药物耐药的细胞群体中的细胞毒性。我们报告了在热疗条件下，对一种耐卡氮芥的人源胶质瘤细胞系U - 373MG和一种对卡氮芥敏感的人源胶质瘤细胞系U - 87MG进行的体外实验。42摄氏度及以上的温度会增强两种细胞系中卡氮芥对细胞的杀伤作用。热敏剂利多卡因会增加热诱导的细胞杀伤，但仅在与治疗性血浆利多卡因水平相当的浓度下有轻微增加。在我们的实验条件下，克服卡氮芥耐药性的最佳策略是热疗、卡氮芥和顺铂联合使用。耐卡氮芥的细胞对顺铂没有交叉耐药性，且卡氮芥和顺铂联合使用具有协同作用。在适度热疗条件（42摄氏度）下，卡氮芥和顺铂以与标准静脉注射剂量后血浆浓度相同的药物浓度联合使用时，可杀死99.4%的耐卡氮芥细胞。使用热疗和药物的临床方案可能需要联合使用两种或更多药物以达到最佳效果。
