Biochemical and molecular mechanisms of cisplatin resistance.
Biochemical and molecular mechanisms of cisplatin resistance.
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DOI：
10.1007/978-1-4615-1173-1_13
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发表时间：
2002
影响因子：
--
通讯作者：
Z. Siddik
中科院分区：
文献类型：
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作者：
Z. Siddik
根据美国国家癌症研究所的DISCOVERY抗癌药物筛选，无机抗肿瘤药物顺铂(顺-二胺-二氯铂（II）；图1)及其类似物可分为至少13个集群区域，每个区域都反映了不同的作用机制1•许多类似物尚未深入研究以揭示其基本作用机制。事实上，近30年来，顺铂作为一种有效的抗肿瘤药物被临床接受，并极大地改变了卵巢癌、睾丸癌和头颈癌的治疗过程，但我们仍在寻找解释顺铂如何起作用的答案。然而，毫无疑问，DNA是顺铂的主要靶点，但了解受损DNA发出的信号如何传递给凋亡或细胞死亡机制仍然是一个有很多争论的主题。了解这一过程可能是确定耐药机制的重要一步，耐药机制继续阻碍顺铂在临床上的治疗性使用。例如，在卵巢癌中，高达70%的初始反应率导致5年生存率仅为15-20%，这一知识可以收集到这种障碍。事实上，大多数（80-85%）患者复发，由于获得性耐药，对进一步顺铂治疗无效。同样，小细胞肺癌患者的复发率可高达95% 5。对耐药机制的了解，要么是肿瘤固有的，要么是药物暴露后获得的，对于确定合理设计类似物的靶点也至关重要。然而，到目前为止，感兴趣的类似物主要是通过包括合成和筛选练习在内的艰苦的经验努力确定的。
According to the DISCOVERY Anticancer Drug Screen of the National Cancer Institute in the USA, the inorganic antitumor agent cisplatin (cis-diammine-dichloro-platinum (II); Figure 1) and its analogs fall into at least 13 clustered regions, each reflecting a distinct mechanism of action 1• Many of these analogs have not been investigated in depth to unravel their fundamental mechanism of action. Indeed, almost 30 years after its clinical acceptance as a potent antitumor drug, which has dramatically changed the course of treatment of ovarian, testicular and head and neck cancers2, we are still searching for answers to explain how cisplatin works. There is no doubt, however, that DNA is the primary target of cisplatin3, but understanding how signals emanating from the damaged DNA are relayed to the apoptotic or cell death machinery is still a subject of much debate. An understanding of this process can be an important step toward defining mechanisms of resistance, which continues to impede the curative use of cisplatin in the clinic. This impediment can be gleaned from the knowledge that in ovarian cancer, for instance, the initial response rate of up to 70% leads to a 5-year survival rate of only 15-20% 4. Indeed, the majority (80-85%) of patients relapse and fail to respond to further treatment with cisplatin as a result of acquired drug resistance. Similarly, in patients with small cell lung cancer, the relapse rate can be as high as 95% 5. Knowledge of resistance mechanisms, which are either intrinsic to the tumor or acquired following drug exposure, is also of paramount importance in defining targets for the rational design of analogs. So far, however, analogs of interest have been identified largely through painstaking empirical efforts involving synthesis and screening exercises.