New cisplatin analogues in development. A review

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)