Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect

The literature on the anti-neoplastic effects of Pt drugs provides substantial evidence that free radical may be involved in the formation of Pt-DNA adducts and other cytotoxic effects. The conditions specific to cancerous tumours are more conducive to free radical mechanisms than the commonly accepted hydrolysis nucleophilic-electrophilic mechanism of Pt-DNA adduct formation. Molecular orbital studies of the adiabatic attachment of hydrated electrons to Pt drugs reveal that there is a significant lengthening of the Pt-X bond (where X is Cl, O in cisplatin, carboplatin and some pyrophosphate-Pt drugs but not oxaliplatin) in the anion radical species. This observation is consistent with a dissociative electron transfer (DET) mechanism for the formation of Pt-DNA adducts. A DET reaction mechanism is proposed for the reaction of Pt drugs with guanine which involves a quasi-inner sphere 2 electron transfer process involving a transient intermediate 5 co-ordinated activated anion radical species {R2Pt-Cl(G)(Cl)center dot}*(-) (where R is an ammine group, and G is guanine) and the complex has an elongated Pt-Cl (or Pt-O) bond. A DET mechanism is also proposed when Pt drugs are activated by reaction with free radicals such as HO center dot, CO3 center dot(-), O-2 center dot(-) but do not react with DNA bases to form adducts, but form Pt-protein adducts with proteins such ezrin, FAS, DR5, TNER1 etc. The DET mechanism may not occur with oxaliplatin. (C) 2016 Elsevier Inc. All rights reserved.