Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Topology effect for corehistone-cis-DDP-DNA model: Topological transformation of cis-diamminedichloroplatinum (II)-DNA adducts by DNA topoisomerase I

S Kobayashi MD, A Tanaka

Departments of Analytical Chemistry of Medicines, Showa Pharmaceutical University, Machida, Tokyo, Japan,

AIM: Much attention has been paid by chemists, pharmacologists, and clinicians for inorganic antitumor drug, cis-diamminedichloroplatinum(II) (Pt(NH3)2Cl2, cis-DDP) and the other platinum complex derivatives which are most effective as drugs for cancer chemotherapy. Although cis-DDP is widely used as a chemotherapeutic agent, the stereoisomer trans-diamminedichloroplatinum(II)(trans-DDP) is inactive. The working mechanism of cis-DDP is generally believed to be binding to cellular DNA, and three binding modes have been reported on the binding models; (i)inter-molecular crosslink, (ii)intra-molecular crosslink, and (iii)monofunctional links, etc. However, the working mechanism of its effects remains uncertain, because it is mostly due to a lack of evidence of the tertiary conformation (or structure) details of cis-DDP—DNA adducts in the cells. Recently, we have reported the productions of the topological isomers such as catenane and trefoil by treatment of cis-DDP-ccDNA adducts with DNA topoisomerase I(Topo I). Our new ideas on the topological changes of cis-DDP-DNA adducts by Topo I would offer much more information of the tertiary structures and shapes of the adducts in cells. METHODS: We report here the reaction between histone-cis-DDP-DNA adducts and Topo I, as a new model of Topo I reaction in the cells using a corehistone-cis-DDP-liear DNA adducts system. RESULTS: Based on our experimental findings, the yields of a mini closed circular DNA and pseudo trefoil DNA, etc. were observed under the electron microscopy analysis. CONCLUSION: Our results suggest that the intra-twisted looped DNA produced by treatment of cis-DDP with DNA is an important intermediate in the products formed by unique topological ( and pseudo topological) transformation.

KEY WORDS: inorganic antitumor drugs.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on chemotherapy.