Current status of trans-platinum compounds in cancer therapy

Most of the structure/activity rules emerged from the initial studies by Ro senberg and Cleare and Hoeschele have now been questioned. Specifically: (i ) trans compounds are inactive, (ii) charged compounds are inactive, (iii) complexes having only one leaving group are inactive, (iv) only complexes w ith two amine ligands, each carrying at least one H atom, are active. Excep tions to the first of these rules will be the subject of this article. Thes e 'exceptions' which frequently show activity against cisplatin resistant t umour cells, fall in four classes: (1) trans-[PtCl2(L)(L ')] with L and/or L ' = pyridine-like ligands; (2) platinum(IV) complexes of formula trans-[P tCl2X2(L)(L ')] with X = hydroxide or carboxylate, L = ammine, and L ' = am ine: (3) trans-[PtCl2(L)(L ')] with L = alkyl-substituted amine and L ' = i sopropylamine: and (4) trans-[PtCl2(L)(L ')] with L and/or L ' = iminoether . Greater inertness in biological medium appears to be a common feature of these compounds. Increased binding affinity for alternating purine-pyrimidi ne sites and enhanced interstrand cross-linking ability was found for the f irst and third class of compounds. Inter-strand cross-links and single-stra nd breaks were both proposed as cytotoxic lesions for the platinum(IV) spec ies which presumably require reduction to platinum(II) prior to their inter action with DNA. Finally, stable monofunctional adducts with duplex DNA, ca using unique local distortions in DNA which are able to inhibit in vitro DN A and RNA synthesis, were found for platinum-iminoether complexes. The rece nt development of new highly active platinum based drugs that do not fit th e classical structure-activity rules indicates the need for a reappraisal o f these rules. It is unlikely that any new widely applicable relationship w ill emerge. All of which goes to show that serendipity still contributes mu ch to the study of Pt drugs, which is only appropriate given how they began . (C) 2001 Elsevier Science B.V. All rights reserved.