Kampinga H H, Konings A W, Evers A J, Brunsting J F, Misfud N, Anderson R L
Department of Radiobiology, University of Groningen, Netherlands.
Int J Radiat Biol. 1997 Mar;71(3):315-26. doi: 10.1080/095530097144201.
Recently, randomized phase III trials have indicated that hyperthermia combined with radiation leads to significantly better tumour control of certain malignancies than does radio-therapy alone. Yet, the full capacity of such combined treatments might not have been optimally exploited as in vitro data indicate that repeated beating of cells can result in either the development of a transient heat resistance (thermotolerance) and/or the selection/induction of a stable heat resistant cell population. Although the mechanism of thermotolerance and its effect on thermo-radiotherapy has been studied extensively, little data are available on the mechanism of stable heat resistance and its impact on combined heat and radiation treatments. In the current study, a comprehensive analysis was made of the differences and similarities between thermotolerance (TT) and stable heat resistance (TR) in terms of the mechanism of resistance to the direct toxic action of heat and in terms of the impact on the extent of thermal radiosensitization. Using heat resistant mutants previously derived from a murine radiation-induced fibrosarcoma (RIF-1), it was observed that these cells were resistant to protein denaturation and aggregation in the cytoplasmic/membrane compartment (measured by ESR (electron spin resonance) analysis and by in situ thermal denaturation of the foreign firefly luciferase targeted to the cytoplasm) but not in the nuclear compartment (measured by TX-100 insoluble nuclear proteins and by in situ thermal denaturation of luciferase targeted to the nucleus). RIF-1-TT cells, in contrast, were resistant for a 1 end-points tested. The lack of protection of nuclear heat damage in the RIF-TR cells could not be explained by a failure of one or more of the HSP70 isoforms to enter the nuclei of these cells. In relation to the absence or presence of heat resistance in the nucleus, the extent of heat radiosensitization was reduced in RIF-1-TT but not RIF-TR cells. This implies that resistance for heat killing is not necessarily accompanied by a reduction in the ability of heat to enhance the cellular radiosensitivity. The data indicate that the mechanism leading to permanent resistance after repeated heating and the mechanism causing thermotolerance may share common features but are in part different.
最近，随机III期试验表明，热疗联合放疗对某些恶性肿瘤的肿瘤控制效果明显优于单纯放疗。然而，这种联合治疗的全部潜能可能尚未得到最佳发挥，因为体外数据表明，细胞的反复受热可导致瞬时耐热性（热耐受）的产生和/或稳定耐热细胞群的选择/诱导。尽管对热耐受的机制及其对热放疗的影响已进行了广泛研究，但关于稳定耐热性的机制及其对热与放疗联合治疗的影响的数据却很少。在本研究中，从热抵抗的直接毒性作用机制以及对热放射增敏程度的影响方面，对热耐受（TT）和稳定耐热性（TR）之间的异同进行了全面分析。利用先前从鼠辐射诱导纤维肉瘤（RIF-1）获得的耐热突变体，观察到这些细胞在细胞质/膜区室（通过电子自旋共振（ESR）分析以及靶向细胞质的外源萤火虫荧光素酶的原位热变性测定）对蛋白质变性和聚集具有抗性，但在核区室（通过TX-100不溶性核蛋白以及靶向细胞核的荧光素酶的原位热变性测定）则不然。相比之下，RIF-1-TT细胞对所测试的1个终点具有抗性。RIF-TR细胞中核热损伤缺乏保护作用，不能用一种或多种HSP70亚型未能进入这些细胞的细胞核来解释。关于细胞核中耐热性的有无，RIF-1-TT细胞的热放射增敏程度降低，而RIF-TR细胞则不然。这意味着对热杀伤的抗性不一定伴随着热增强细胞放射敏感性能力的降低。数据表明，反复加热后导致永久抗性的机制与引起热耐受的机制可能有共同特征，但部分不同。
