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New Platinum Agents

A Comparison in Ovarian Cancer

  • Review Article
  • Drug Therapy
  • Published:
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Summary

Compared with most solid tumours in humans, ovarian cancer may be considered a relatively chemosensitive disease. The platinum-based drug, cisplatin, has significantly enhanced long term survival (by more than 10%), though there remains scope for considerable improvement.

Carboplatin is equiactive with, but substantially less toxic than, cisplatin (especially in terms of nephrotoxicity, effects on the gastrointestinal tract and neurotoxicity). Long term data are emerging from randomised trials that support the replacement of cisplatin by carboplatin in the first-line treatment of ovarian cancer.

Iproplatin is also less toxic than cisplatin, but is more toxic and less active than carboplatin. A further advance in reducing patient morbidity associated with platinum-based chemotherapy may come from the first orally administrable platinum complex, JM216, which has recently been introduced into clinical trials.

Current and future platinum drug discovery initiatives should focus on circumventing mechanisms of tumour resistance to cisplatin. Laboratory studies have identified 3 major mechanisms of resistance: reduced drug transport, enhanced intracellular detoxification (through glutathione and/or metallothioneins) and enhanced DNA removal (or tolerance) of platinum-DNA adducts (the long assumed critical lesions leading to cell kill).

Platinum complexes based on the 1,2-diaminocyclohexane carrier ligand (such as oxaliplatin and tetraplatin) have recently entered clinical trials, having been shown to circumvent cisplatin resistance in murine leukaemia tumour models. Clinically, they have shown little evidence of activity in cisplatin-resistant disease and appear to cause severe neurotoxicity. Other platinum-based drugs currently in clinical trials are predominantly carboplatin-like, and have not, to date, shown evidence of overcoming resistance to cisplatin.

JM216, the orally active platinum drug, may confer activity in cisplatinresistant disease as a result of decreased drug uptake. Newly discovered trans platinum complexes such as JM335, which are active in vivo in preclinical tumour models, may represent leads to the discovery of a new generation of platinum-based drugs with a broader spectrum of clinical activity than either cisplatin or carboplatin.

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Authors and Affiliations

  1. CRC Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, England

    Lloyd R. Kelland

  2. Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia

    Mark J. McKeage

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Kelland, L.R., McKeage, M.J. New Platinum Agents. Drugs & Aging 5, 85–95 (1994). https://doi.org/10.2165/00002512-199405020-00002

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