Bruno T, Gentile F P, Di Padova M, Antonucci E, Rubiu O, Dolo V, Pavan A, Floridi A
Laboratory for Cell Metabolism and Pharmacokinetics, Regina Elena Institute for Cancer Research, Rome, Italy.
Oncol Res. 1998;10(3):143-50.
The effect of hyperthermia and bupivacaine, alone and in combination, on the clonogenic activity of a human melanoma cell line was investigated. The time-temperature relationship of exponentially growing cells was defined in the range of 41-45 degrees C. All the survival curves were exponential and the Arrhenius plot was linear over the temperature range tested. The survival curve of bupivacaine-treated cells was also exponential after an initial shoulder. Bupivacaine affected cell survival mainly through an ATP depletion because of deep alterations of mitochondria, essentially due to changes in the physical state of membrane lipids. The analysis of the interaction between hyperthermia and bupivacaine, performed with an isobolar method, demonstrated a synergism of response at all combinations tested, but only with simultaneous exposure. Such a response did not depend on an impairment of the energy-yielding processes, but may be ascribed to combined effects of both agents on cell structure and function. The hyperthermic enhancement achieved by low bupivacaine concentrations allowed to achieve a preestablished cell killing with a reduced exposure time (e.g., 50 min) and with a temperature (42 degrees C) generally accepted as clinically achievable. Therefore, a combined modality in which local treatment with bupivacaine was coupled to local heating could result in high local damage with reduced systemic complications.
研究了热疗和布比卡因单独及联合应用对人黑色素瘤细胞系克隆形成活性的影响。在41-45摄氏度范围内确定了指数生长细胞的时间-温度关系。所有存活曲线均为指数型，且在测试温度范围内阿累尼乌斯图呈线性。布比卡因处理的细胞在初始肩部后存活曲线也呈指数型。布比卡因主要通过线粒体深度改变导致的ATP耗竭影响细胞存活，这主要是由于膜脂物理状态的变化。采用等效应线法对热疗和布比卡因之间的相互作用进行分析，结果表明在所有测试组合中均存在协同反应，但仅在同时暴露时出现。这种反应不依赖于能量产生过程的损害，可能归因于两种药物对细胞结构和功能的联合作用。低浓度布比卡因实现的热增强效应使得在减少暴露时间（如50分钟）和采用通常认为临床上可达到的温度（42摄氏度）的情况下达到预先设定的细胞杀伤效果。因此，将布比卡因局部治疗与局部加热相结合的联合治疗方式可能会导致局部高度损伤，同时减少全身并发症。
