文章：

以铂为基础的癌症化疗的复苏

The resurgence of platinum-based cancer chemotherapy

原文发布日期：2007-07-12

DOI: 10.1038/nrc2167

类型: Review Article

开放获取: 否

要点：

1. Since the accidental discovery of its biological properties over 40 years ago, cisplatin has made a major impact in the chemotherapeutic treatment of testicular and ovarian cancers and is still widely used today.
2. The initial driver for further platinum-drug development was the discovery of the severe safety issues that are raised with cisplatin, especially nephrotoxicity. This resulted in the development of carboplatin, which is, broadly speaking, equally effective to cisplatin, but with a more acceptable side-effect profile.
3. The mechanism of action of cisplatin (and carboplatin) involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis.
4. Much is now understood as to how tumours all too commonly exhibit resistance to cisplatin, either intrinsically or as acquired during courses of therapy. Major mechanisms include: decreased membrane transport of the drug, increased cytoplasmic detoxification, increased DNA repair, and increased tolerance to DNA damage.
5. The second driver for new platinum-drug development was to circumvent mechanisms of resistance, and thereby broaden the clinical utility of this class of agents. These efforts have resulted in oxaliplatin (active in patients with colorectal cancer), satraplatin (the first orally administered platinum drug, which shows promise in patients with prostate cancer) and picoplatin.
6. Improved delivery of platinum drugs to tumours is being studied in early clinical trials using liposomal-based or co-polymer-based products, as well as by the use of localized, intraperitoneal administration of cisplatin or carboplatin in patients with ovarian cancer.
7. It might also be possible to circumvent platinum-drug resistance in the clinic through modulating resistance mechanisms; for example, those involving increased glutathione or loss of DNA mismatch repair.

要点翻译：

1. 自40多年前偶然发现其生物学特性以来，顺铂在睾丸癌和卵巢癌的化疗中产生了重大影响，至今仍被广泛使用。
2. 推动铂类药物进一步研发的最初动力，是发现顺铂引发的严重安全性问题（尤其是肾毒性），这促使卡铂问世。一般来说，卡铂与顺铂疗效相当，但具有更可接受的副作用特征。
3. 顺铂（及卡铂）的作用机制涉及与嘌呤DNA碱基的共价结合，主要导致细胞凋亡。
4. 目前对肿瘤通常表现出的顺铂耐药性（无论是先天耐药还是治疗过程中获得的耐药）已有较深理解。主要机制包括：药物膜转运减少、胞浆内解毒作用增强、DNA修复增加以及对DNA损伤的耐受性提高。
5. 新铂类药物研发的第二个驱动力是规避耐药机制，从而拓宽该类药物的临床应用。这些努力催生了奥沙利铂（对结直肠癌患者有效）、沙铂（首个口服铂类药物，对前列腺癌患者显示出潜力）和吡铂。
6. 通过基于脂质体或共聚物的产品，以及局部腹腔给药顺铂或卡铂治疗卵巢癌患者，改善铂类药物肿瘤递送的研究正在早期临床试验中进行。
7. 临床上也可能通过调节耐药机制来规避铂类耐药，例如针对涉及谷胱甘肽增加或DNA错配修复缺失的机制。

英文摘要：

The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin — a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin — was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.

摘要翻译： 

顺铂抗癌特性的意外发现及其在20世纪70年代的临床应用，是抗癌药物成功史上的重要里程碑。尽管第二代类似物卡铂——安全性更高但活性谱与顺铂相似——于20世纪80年代问世，后续进展却在多年间趋于缓慢。然而，近年来，铂类药物重新受到关注。关键进展包括阐明肿瘤对这些药物的耐药机制、新型铂类制剂（奥沙利铂、沙曲铂和吡铂）的问世，以及将铂类药物与耐药调节剂或新型分子靶向药物联合的临床研究。

原文链接：

The resurgence of platinum-based cancer chemotherapy