McKay M J, Kefford R F
University of Sydney Westmead Center.
Int J Radiat Oncol Biol Phys. 1995 Jan 15;31(2):345-52. doi: 10.1016/0360-3016(94)e0147-c.
Radioresistance is a significant clinical problem in advanced malignant melanoma and many melanoma cell lines show a radioresistant acute x-ray survival response in vitro. Given that the DNA double strand break is the lesion most closely correlated with x-ray induced cell lethality, differences in the induction and rejoining of these lesions may account for the radioresistance of some human melanoma cell lines.
The above hypothesis was tested using pulsed field gel electrophoresis to measure x-ray induced DNA double strand break induction and rejoining in four human melanoma cell lines: MM138, MM170, MM96-L and HT 144.
The MM138, MM170 and MM96-L cell lines were characterized in vitro by low alpha/beta ratios and broad x-ray survival curve shoulders. MM138 and MM170 were the most radioresistant and MM96-L had intermediate sensitivity. In contrast, HT144 was markedly x-ray sensitive, despite retaining a shoulder and like the other lines, having a low alpha/beta ratio. There were no significant differences in DNA double strand break induction between the cell lines, and thus no correlation existed between DNA double strand break induction and radiosensitivity. Consistent with the shoulders on the x-ray survival curves, all four cell lines showed efficient DNA double strand break rejoining. Highly efficient DNA double strand break rejoining could account for the radioresistance of one of the melanoma lines (MM138). For example, MM138 had rejoined 50% of the induced DNA double strand breaks by 5.5 min compared to 13-17 min for the other three cell lines. The development of postirradiation apoptosis was effectively excluded as the cause of the marked radiosensitivity of the HT144 cell line.
Other factors (such as lesion repair fidelity or differential lesion tolerance) underlie the differences in the intrinsic radiosensitivity between these melanoma cell lines.
放射抗性是晚期恶性黑色素瘤中的一个重要临床问题，许多黑色素瘤细胞系在体外表现出放射抗性急性X射线存活反应。鉴于DNA双链断裂是与X射线诱导的细胞致死率最密切相关的损伤，这些损伤在诱导和重新连接方面的差异可能解释了一些人黑色素瘤细胞系的放射抗性。
使用脉冲场凝胶电泳来测量四种人黑色素瘤细胞系（MM138、MM170、MM96-L和HT 144）中X射线诱导的DNA双链断裂的诱导和重新连接，对上述假设进行了检验。
MM138、MM170和MM96-L细胞系在体外的特征是低α/β比值和宽X射线存活曲线肩部。MM138和MM170的放射抗性最强，MM96-L具有中等敏感性。相比之下，HT144对X射线明显敏感，尽管保留了一个肩部，并且与其他细胞系一样，具有低α/β比值。各细胞系之间在DNA双链断裂诱导方面没有显著差异，因此DNA双链断裂诱导与放射敏感性之间不存在相关性。与X射线存活曲线上的肩部一致，所有四种细胞系都显示出有效的DNA双链断裂重新连接。高效的DNA双链断裂重新连接可以解释其中一种黑色素瘤细胞系（MM138）的放射抗性。例如，与其他三种细胞系的13 - 17分钟相比，MM138在5.5分钟时已重新连接了50%的诱导DNA双链断裂。照射后凋亡的发生被有效排除为HT144细胞系显著放射敏感性的原因。
其他因素（如损伤修复保真度或不同的损伤耐受性）是这些黑色素瘤细胞系之间内在放射敏感性差异的基础。
