Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy

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Platinum DNA Chemistry

  • Stephen J. LippardAffiliated withDepartment of Chemistry, Massachusetts Institute of Chemistry

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This article delineates the chemistry of platinum antitumor drugs and related compounds with DNA. The evidence that DNA is primary target for cisplatin has been presented in detail elsewhere.1 Displayed in Figure 1 are structural representations of the platinum complexes to be discussed. Cisplatin and carboplatin are the only two currently approved for use clinically. They follow the classical structure-function relationships,2 being able to form cross-links at two cis positions in their coordination spheres, in contrast to the monofunctional complexes [Pt(dien)Cl]+ and [Pt(NH3)3Cl]+, and the bifunctional trans-[Pt(NH3)2Cl2] analogue. Two promising candidates for clinical trials are included, “triamine” complexes [Pt(NH3)2(4-X-py)Cl]+ (X = Me, Br) which violate two of the classical rules in being cationic and monofunctional,3 and a complex, cis-[Pt(NH3)(C6H11NH2)Cl2], that is a likely metabolite of a new class of orally active antitumor platinum(IV) compounds.4 The other compounds all have the ability to bind to DNA in whole or in part by intercalation. Since some of the compounds used in combination chemotherapy with cisplatin are intercalators, bleomycin being one example, it is important to understand their ternary interactions with DNA. Only the results of experiments carried out in vitro are included in the discussion, although we caution that there will be some differences from the reactions that take place in living cells.5