Reactivity of DNA and cis-Diamminedichloroplatinumul(II) in the Presence of Intercalating Agents

Abstract : The antitumor drug cis-diamminedichloroplatinum(II) (cis-DDP) is assumed to exhibit its toxicity by reacting with cellular DNA. Lesions produced in DNA have been characterized as bifunctional adducts including mainly intrastrand and interstrand cross-links. It is not yet known which lesion(s) is(are) responsible for selective destruction of tumor cells1–3. Drugs known to bind to DNA such as doxorubicin or bleomycin are commonly used therapeutically in combination with cis-DDP4. In vitro several studies have shown the mutual influence of cis-DDP and drugs binding to DNA5–11. One purpose of our work is to better understand how the binding of cis-DDP can be altered by the presence of other drugs interacting also with DNA. In this paper, we first show that RNA polymerases are a convenient tool to detect the adducts formed in the in vitro reaction between DNA and cis-DDP. In particular, we find that the interstrand adducts are formed at the d(GC) sites. Then, we show that a new kind of adduct, a DNA-monocoordinated complex, is formed when the reaction of platination is done in the presence of some intercalating agents. In this reaction, the DNA double helix first favors the formation of the new adduct and then favors the release of a platinum derivative. These results are discussed in relation with a catalytic activity of the DNA double helix.
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Frederic Gaucheron, Marie-Agnes Lemaire, Jean-Marc Malinge, Annie Schwartz, Marc Leng. Reactivity of DNA and cis-Diamminedichloroplatinumul(II) in the Presence of Intercalating Agents. Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy, Springer US, pp.73-79, 1991, 978-1-4899-0740-0. ⟨hal-02134699⟩

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