Further Objectives in the Development of Platinum Drugs

Cisplatin, either as a single agent or, more usually, in combination therapy, is active against several human tumours, particularly those of genito-urinary origin. While it has undoubtedly broadened the spectrum of tumours which are amenable to chemotherapy, its contribution is still quite limited. While cisplatin has improved responses for cervix, bladder, prostate and head and neck cancer, it has, to date, only made a major impact on long term survival for ovarian and, particularly, testicular tumours(1). Also, its efficacy is somewhat compromised by the occurrence of major toxic side effects such as nephrotoxicity, myelosuppression, nausea and vomiting and ototoxicity. Although hydration techniques have reduced nephrotoxicity, which is the major dose limiting factor, higher doses can sometimes result in the appearance of peripheral neuropathy symptoms after several treatments. This has stimulated efforts to identify alternative complexes which retain the useful anti-tumour properties of cisplatin while having reduced toxicity. Studies have concentrated on complexes of the type cis-[PtX2A2] (where A2 = two monodentate or one bidentate amine ligand and X2 = two monodentate or one bidentate anionic ligand). The chemistry of such species has been discussed in detail elsewhere(2) but it is sufficient here to emphasise that the strength of the Pt-N (amine) bond is a dominating feature which means that the X groups are relatively reactive compared to the A groups which are inert to substitution.