Hydes P C, Russell M J
Johnson Matthey Technology Centre, Reading, United Kingdom.
Cancer Metastasis Rev. 1988 Apr;7(1):67-89. doi: 10.1007/BF00048279.
In the past 4 years substantial progress has been made in the development of platinum cancer chemotherapy. A number of drug candidates have undergone clinical trials and one 'second generation' platinum drug, carboplatin, has been approved for use in the treatment of ovarian and small cell lung cancer. This review covers the major developments since the last international conference on Platinum Chemotherapy in Vermont, and attempts to highlight the primary factors that appear to be influencing the synthesis and screening of potential third generation platinum drugs. A predominant feature in the evaluation of analogues has been the emphasis on chelating diamine complexes, in particular those of diaminocyclohexane, which show activity in L1210 tumours that are resistant to cisplatin, and the use of a wide range of carboxylate ligands as a means of circumventing solubility and toxicity problems inherent in the parent compounds. There has also been an increased effort in studies relating to complexes containing mixed amines and functionalised amines, building on the assumption, which remains valid to date, that two amines are a necessary requirement for anti-tumour activity. Efforts have also been made to address the use of complexes containing biologically active ligands, and the concept of targeting compounds to specific organs and formulating drugs to achieve more specific activity or controlled release of drugs with lower toxicities. These may provide a viable route to drugs that can be administered more easily, for example by an oral route, or show a different spectrum of activity. However, it may prove difficult to adequately characterise these more complex systems. The major problem encountered in evaluating cisplatin analogues, as with other prospective cancer drugs, is finding reproducible anti-tumour screens that are predictive of the behaviour of the drugs in the clinic. Progress is being made in the development of sensitive and resistant human tumour xenograft lines and this area should be monitored with interest, as it may provide a key to the development of a future platinum drug, hopefully with a wider range of activity than either cisplatin or carboplatin.
在过去4年里，铂类癌症化疗药物的研发取得了重大进展。许多候选药物已进入临床试验阶段，一种“第二代”铂类药物——卡铂，已被批准用于治疗卵巢癌和小细胞肺癌。本综述涵盖了自上次在佛蒙特州召开的铂类化疗国际会议以来的主要进展，并试图突出那些似乎影响潜在第三代铂类药物合成与筛选的主要因素。在类似物评估中，一个主要特点是强调螯合二胺配合物，特别是二氨基环己烷类配合物，它们在对顺铂耐药的L1210肿瘤中显示出活性，并且使用了多种羧酸盐配体，以此来规避母体化合物固有的溶解性和毒性问题。在含混合胺和官能化胺的配合物研究方面也加大了力度，这基于一个至今仍然有效的假设，即两个胺是抗肿瘤活性的必要条件。人们还努力研究含生物活性配体的配合物，以及将化合物靶向特定器官和设计药物以实现更特异的活性或更低毒性药物控释的概念。这些可能为更容易给药的药物，例如口服给药，提供一条可行的途径，或者展现出不同的活性谱。然而，可能难以充分表征这些更复杂的体系。与其他潜在的癌症药物一样，评估顺铂类似物时遇到的主要问题是找到可重复的抗肿瘤筛选方法，以预测药物在临床中的表现。在敏感和耐药的人肿瘤异种移植系的开发方面正在取得进展，这个领域值得关注，因为它可能为未来铂类药物的开发提供关键，有望获得比顺铂或卡铂活性范围更广的药物。
