The Clinical Development of the Oral Platinum Anticancer Agent JM216
The platinum antitumour agents cisplatin and carboplatin have brought significant benefits to the treatment of a wide variety of malignancies1. However, drug resistance remains a problem and toxicity can be significant. Where the aim of treatment is symptom palliation, which is more often than not the case, it is important to consider the side effects and convenience of treatment. A collaborative programme of research into new platinum anticancer agents conducted by The Institute of Cancer Research and Johnson Matthey Technology has focused on the twin objectives of developing agents which lack cross-resistance with cis- and carboplatin and agents which can be given by the oral route. A key lead was the identification of the ammine/amine platinum (IV) dicarboxylates2 which not only exhibit good oral bioavailability but also show activity in certain cisplatin resistant human ovarian cancer cell lines in vitro.3 The specific aims of the oral development programme were to identify an agent with good oral bioavailability, low emetogenicity, no significant specific organ toxicity, such as nephrotoxicity, ototoxicity, or neurotoxicity, and dose limiting myelosuppression. These selection criteria were used to identify bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV), or JM216 for clinical development4,5 (Fig. 1). Of these, one of the most stringent was emesis, which was tested in a ferret model in comparison with a number of other agents, especially cisplatin. Preclinical studies of neurotoxicity were conducted in parallel with the clinical trials and while confirming the lack of neurotoxicity compared with cisplatin and ormaplatin they did not play a part in the selection process.6 The phase I studies with JM216 demonstrated that the preclinical objectives had been amply fulfilled7 and phase II studies are currently underway to evaluate its antitumour efficacy.
KeywordsArea Under Curve Human Ovarian Cancer Cell Line Interpatient Variation Good Oral Bioavailability Free Platinum
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