Hatton D H, Mitchell D L, Strickland P T, Johnson R T
Department of Zoology, University of Cambridge, United Kingdom.
Cancer Res. 1995 Jan 1;55(1):181-9.
A fundamental issue in understanding melanoma is to seek the basis for the cellular resistance to DNA damaging agents, which is manifested in vivo as pronounced tumor resistance to therapeutic agents. The published consensus on melanoma has been that exaggerated postreplication recovery (PRR), rather than excision repair, underlies the unusual damage-resistance phenotype. We examined the resistance to the model DNA damaging agent, UV-C, of subclones derived from a human metastatic melanoma cell line. The clones essentially fall into two groups: one with normal and the other with enhanced resistance. We exploited this range to investigate the interrelationships between replication, transcription, and repair of DNA after UV irradiation. Subclones resistant to UV killing were indeed found to possess enhanced rates of PRR and were coresistant to cisplatin. However, we now report an overall elevation of photoproduct repair in both melanoma groups compared to nonmelanoma controls and conclude that this accounts for the resistant melanoma phenotype, including that of enhanced PRR. Repair enhancement may explain chemoresistance, while loss of efficiency of certain functions, such as PRR, due to the intrinsic genetic lability of tumor cells, may generate the class of melanoma subclones exhibiting only normal resistance.
理解黑色素瘤的一个基本问题是寻找细胞对DNA损伤剂产生抗性的基础，这种抗性在体内表现为肿瘤对治疗剂具有显著抗性。关于黑色素瘤已发表的共识是，异常的损伤抗性表型的基础是复制后修复（PRR）过度，而非切除修复。我们研究了源自人转移性黑色素瘤细胞系的亚克隆对模型DNA损伤剂紫外线C（UV-C）的抗性。这些克隆基本上分为两组：一组抗性正常，另一组抗性增强。我们利用这一范围来研究紫外线照射后DNA复制、转录和修复之间的相互关系。确实发现对紫外线杀伤具有抗性的亚克隆具有更高的PRR速率，并且对顺铂也具有交叉抗性。然而，我们现在报告，与非黑色素瘤对照相比，两个黑色素瘤组的光产物修复总体上有所提高，并得出结论，这解释了抗性黑色素瘤表型，包括增强的PRR表型。修复增强可能解释了化学抗性，而由于肿瘤细胞固有的遗传不稳定性导致某些功能（如PRR）效率丧失，可能产生仅表现出正常抗性的黑色素瘤亚克隆类别。
