Weiss Raymond B, Christian Michaele C
Section of Medical Oncology, Walter Reed Army Medical Center, Washington, DC, 20307, USA.
Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Drugs. 1993 Sep;46(3):360-377. doi: 10.2165/00003495-199346030-00003.
Cisplatin was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Since the early seminal work in the preclinical and clinical development of this drug, several thousand analogues have been synthesised and tested for properties that would enhance the therapeutic index of cisplatin. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. However, carboplatin has afforded benefit only in reducing some cisplatin toxicities; it has not enlarged the spectrum of platinum-sensitive cancers, nor has it proved active in cisplatin-resistant cancers. The major obstacle to the efficacy of cisplatin or carboplatin is platinum resistance, either innate or acquired. The mechanisms of this resistance have been under intense study, and many of the cisplatin analogues synthesised in the past decade have been designed specifically with the hope of overcoming platinum resistance. The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life. Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS)
顺铂于20世纪60年代被发现具有细胞毒性，到20世纪70年代末，它已成为生殖细胞癌全身治疗的关键成分。自从该药物在临床前和临床开发方面开展早期开创性工作以来，已合成了数千种类似物，并对其能提高顺铂治疗指数的特性进行了测试。其中约13种类似物已在临床试验中进行评估，但只有一种（卡铂）比顺铂具有明确优势并获得全球批准。然而，卡铂仅在降低某些顺铂毒性方面有好处；它并未扩大铂敏感癌的范围，在顺铂耐药癌中也未显示出活性。顺铂或卡铂疗效的主要障碍是铂耐药，包括先天耐药和获得性耐药。这种耐药机制一直在深入研究，过去十年中合成的许多顺铂类似物都是专门为克服铂耐药而设计的。铂配合物的细胞毒性活性机制也得到了深入研究。最近合成的类似物旨在以不同于顺铂和卡铂的方式与DNA相互作用，以期找到具有更高或更广泛抗肿瘤疗效谱的新结构。最近，为了提高患者生活质量，已合成了具有抗肿瘤活性、口服后能有效吸收的水溶性铂配合物。目前全球有九种铂类似物正在进行临床试验（奥马铂[四铂]、奥沙利铂、DWA2114R、恩洛铂、洛铂、CI-973[NK-121]、254-S、JM-216和脂质体包裹的顺式-双新癸酸酯-反式-R，R-1，2-二氨基环己烷铂（II）[LNDDP]）。其中一些类似物只是为了降低顺铂毒性和/或无需强制水化和利尿即可给药（卡铂已经可以做到这一点）而进行的尝试。其他的是“第三代”配合物，在临床前研究中显示与顺铂有有限的交叉耐药或无交叉耐药。目前正在对它们进行临床测试，特别关注这一非常理想的特性。（摘要截选至400字）
