Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance
Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance
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DOI：
10.1016/s0162-0134(99)00141-5
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发表时间：
1999-10-01
影响因子：
3.9
通讯作者：
Judson, IR
中科院分区：
文献类型：
--
作者：
Kelland, LR;Sharp, SY;Judson, IR
近20年来，新的含铂抗癌药物的发现和开发是萨顿癌症研究所抗癌药物开发的一个组成部分。作为与约翰逊万丰（后来的AnorMED）化学家合作的一部分，发现了四种主要的新铂类药物，其中三种已进入临床试验。早期的研究导致了毒性较小的类似物卡铂和第一种口服铂类药物JM 216的临床开发。近年来，焦点一直集中在两种旨在克服肿瘤对顺铂耐药的主要机制的铅络合物上：JM 335（反式氨（环己基胺二氯二氢）铂（IV）），一种活性反式铂络合物;和ZD 0473（顺式氨二氯（2-甲基吡啶）铂（II）），一种空间位阻络合物，对含巯基分子的反应性低于顺铂。JM 335在体外显示出一定程度的获得性顺铂耐药性的规避，并且与顺铂或其顺式异构体相比，在DNA上加合物的基因特异性修复和细胞凋亡诱导率方面表现出独特的细胞药理学特性。ZD 0473目前处于I期临床试验阶段。骨髓抑制是剂量限制性毒性，剂量为130 mg/m2，每3周静脉注射一次，有证据表明具有抗肿瘤活性。已经在体外建立了ZD 0473耐药的人卵巢癌细胞系。已观察到顺铂所述的一些常见耐药机制（药物摄取减少，谷胱甘肽增加），以及在一个细胞系中BCL 2水平增加和DNA错配修复蛋白MLH 1丢失。（C）1999年Elsevier Science Inc. All rights reserved.
The discovery and development of new platinum-containing anticancer drugs have represented an integral part of anticancer drug development at the Institute of Cancer Research, Sutton, over almost 20 years. As part of a collaboration with chemists at Johnson Matthey, later AnorMED, four major new classes of platinum drug have been discovered, three of which have entered clinical trial. Earlier studies led to the clinical development of the less toxic analogue carboplatin and JM216, the first orally administerable platinum drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 (trans-ammine ( cyclohexylaminedichlorodihydroxo) platinum(IV)), an active trans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) platinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular pharmacological properties in comparison to cisplatin or its cis-isomer in terms gene-specific repair of adducts on DNA and the rate of induction of apoptosis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose-limiting toxicity at a dose of 130 mg/m(2) given i.v. every 3 weeks and there has been evidence of antitumour activity. ZD0473-resistant human ovarian carcinoma cell lines have been established in vitro. Some mechanisms of resistance common to those described for cisplatin (decreased drug uptake, increased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the,DNA mismatch repair protein MLH1. (C)1999 Elsevier Science Inc. All rights reserved.