Ongoing and unsaid on oxaliplatin: the hope
Ongoing and unsaid on oxaliplatin: the hope
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DOI：
10.1038/bjc.1998.429
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发表时间：
1998-06-01
影响因子：
8.8
通讯作者：
Cvitkovic, E
中科院分区：
文献类型：
--
作者：
Cvitkovic, E
奥沙利铂是第一种可用的二氨基环己烷铂，在结直肠癌和卵巢癌中具有临床活性。其作用机制被认为与顺铂相似，其主要机制是两个相邻的鸟嘌呤或两个相邻的鸟嘌呤和腺嘌呤加合物之间的链内DNA加合物。正在进行的顺铂作用机制的分子药理学研究表明，铂化加合物可被错配修复系统的蛋白质识别，包括hMLH1和hMSH2基因的产物。DNA错配修复缺陷发生在各种散发性人类癌症中，是遗传性非息肉病性结肠癌的主要遗传因素，也是卵巢癌和其他实体肿瘤中常见的新发或获得性现象。此外，最近有报道称它们是顺铂耐药的一个原因，而不是奥沙利铂耐药的原因，因为二氨基环己烷铂加合物似乎不能被错配修复复合物识别。这些发现解释了奥沙利铂在一些顺铂耐药肿瘤中的活性。此外，奥沙利铂良好的安全性使其成为联合治疗的首选药物，并且已被证明与其他细胞毒性药物，包括5-氟尿嘧啶、顺铂、卡铂、拓扑替康、吉西他滨和CPT-11具有协同作用。几项正在进行的试验的结果尚待公布，但现有数据表明，奥沙利铂在治疗晚期结直肠癌和卵巢癌方面非常有效。有希望的早期结果表明，它对非霍奇金淋巴瘤、乳腺癌和非小细胞肺癌也有效。由于其作用机制、良好的安全性和不同的抗肿瘤活性，奥沙利铂作为一种活性的、多功能的抗肿瘤药物的全部潜力尚未得到充分的探索。
Oxaliplatin, the first available diaminocyclohexane platinum, has clinical activity in colorectal and ovarian cancers. Its mechanism of action is thought to be similar to that of cisplatin, its main mechanism being the intrastrand DNA adduct between two adjacent guanins or two adjacent guanine and adenine adducts. Ongoing molecular pharmacological studies of the mechanism of action of cisplatin suggest that platinated adducts are recognized by proteins of the mismatch repair system, including the products of the hMLH1 and hMSH2 genes. DNA mismatch repair defects occur in a wide variety of sporadic human cancers, are the main genetic factor in hereditary non-polyposis colon cancer and a frequent de novo or acquired phenomenon in ovarian cancer and other solid tumours. Moreover, they have recently been reported to be a cause of resistance to cisplatin but not to oxaliplatin, as diaminocyclohexane platinum adducts do not appear to be recognized by the mismatch repair complex. These findings explain the oxaliplatin activity in some cisplatin-resistant tumours. In addition, the good safety profile of oxaliplatin makes it a drug of choice for combination therapy, and it has been shown to be synergistic with other cytotoxic agents, including 5-fluorouracil, cisplatin, carboplatin, topotecan, gemcitabine and CPT-11.The results of several ongoing trials are awaited, but available data demonstrate that oxaliplatin is highly effective in the treatment of advanced colorectal and ovarian cancers. Promising early results suggest that it is also efficacious in non-Hodgkin's lymphoma, breast and non-small-cell lung cancers. As a result of its mechanism of action, its favourable safety profile and the differential profile of its antitumoral activity, the full potential of oxaliplatin as an active, versatile antitumoral agent is yet to be fully explored.