title: Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect.
abstract: 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)•}*(-) (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•, CO3•(-), O2•(-) but do not react with DNA bases to form adducts, but form Pt-protein adducts with proteins such ezrin, FAS, DR5, TNFR1 etc. The DET mechanism may not occur with oxaliplatin.
authors.affiliation: Eigenenergy, Adelaide, South Australia. Electronic address: cwfong@internode.on.net.
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Fong
mesh_terms: D000838:Anions / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D005609:Free Radicals / Q000009:adverse effects / Q000737:chemistry*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D000077150:Oxaliplatin; D010984:Platinum / Q000737:chemistry*
chemical_list: D000838:Anions; D000970:Antineoplastic Agents; D018736:DNA Adducts; D005609:Free Radicals; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D002945:Cisplatin
keywords: Cellular toxicity; Dissociative electron transfer; Free radicals; Molecular orbital calculations; Pt anti-cancer drugs; Pt-DNA Pt-protein adducts