The resurgence of platinum-based cancer chemotherapy

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Abstract
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. 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. The mechanism of action of cisplatin (and carboplatin) involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis. 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. 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. 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. 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.