Possible Incorporation of Free N7-Platinated Guanines in DNA by DNA Polymerases, Relevance for the Cisplatin Mechanism of Action

Abstract

Cisplatin, cis-diamminedichloroplatinum (II), is one of the most widelyused anticancer drugs. The main cellular target of cisplatin is DNA,where the platinum atom is able to form covalent bonds with the N7 ofpurines. It is commonly accepted that there is a direct attack ofcisplatin on DNA. But it should be noted that, inside cells, free purinebases, which can react with cisplatin, are also available. Free baseshave many functional roles, not least the constitution of buildingblocks for the synthesis of new DNA and RNA molecules. For this reason,under physiological conditions, the erroneous insertion of platinatedbases in the synthesized nucleic acids could compete with direct DNA/RNAplatination. Moreover, due to the lower sterical hindrance offered bysingle nucleobases with respect to nucleic acids, platination isexpected to be even easier for free purines with respect to DNA and RNA.We have recently shown, for the first time, that platinated DNA can beformed in vitro by Taq DNA polymerase promoted incorporation ofplatinated purines, Cytotoxicity tests with {[}Pt(dien)(W-G)], then =diethylenetriamine, G = 5'-dGTP, 5'-dGDP, 5'-GMP, 5'-dGMP, GUO, dGUO,complexes on HeLa cancer cells support this hypothesis of the relativecytotoxicity of {[}Pt(dien)(N7-G)] derivatives being clearly related totheir bioavailability. In vivo platination of free purines before theirincorporation in nucleic acids therefore opens new perspectives inplatinum based antitumour drugs, for a better understanding of both theaction mechanism and the new molecular design.