Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance

The discovery and development of new platinum-containing anticancer drugs h ave represented an integral part of anticancer drug development at the Inst itute of Cancer Research, Sutton, over almost 20 years. As part of a collab oration with chemists at Johnson Matthey, later AnorMED, four major new cla sses of platinum drug have been discovered, three of which have entered cli nical trial. Earlier studies led to the clinical development of the less to xic analogue carboplatin and JM216, the first orally administerable platinu m drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 ( trans-ammine ( cyclohexylaminedichlorodihydroxo) platinum(IV)), an active t rans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) pla tinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular phar macological properties in comparison to cisplatin or its cis-isomer in term s gene-specific repair of adducts on DNA and the rate of induction of apopt osis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose -limiting toxicity at a dose of 130 mg/m(2) given i.v. every 3 weeks and th ere has been evidence of antitumour activity. ZD0473-resistant human ovaria n carcinoma cell lines have been established in vitro. Some mechanisms of r esistance common to those described for cisplatin (decreased drug uptake, i ncreased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the,DNA mismatch repair protein MLH1. (C)1999 Elsev ier Science Inc. All rights reserved.