DNA Adduct Formation by the Anticancer Drug Ellipticine and Its Hydroxy Derivatives in Human Breast Adenocarcinoma MCF-7 Cells

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Title:DNA Adduct Formation by the Anticancer Drug Ellipticine and Its Hydroxy Derivatives in Human Breast Adenocarcinoma MCF-7 Cells
Creators:
Bořek-Dohalská, Lucie
Frei, Eva
Stiborová, Marie
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 69, 3, pp. 603-615
Uncontrolled Keywords:Anticancer drug, DNA adducts, Human cytochrome P450, Human breast cancer MCF-7 cells, Ellipticine, Antineoplastic activity, Activation, Cytotoxicity, <sup>32</sup>P-Postlabeling

Abstract

The cytotoxicity of the antineoplastic agent ellipticine and its 9- and 7-hydroxylated metabolites to human breast adenocarcinoma MCF-7 cells and their ability to generate DNA adducts in these cancer cells were investigated. Ellipticine and its 9-hydroxylated metabolite were found to be toxic to MCF-7 cells with IC<sub>50</sub> values of 1.25 and 3.25 μmol l<sup>-1</sup> for ellipticine and 9-hydroxyellipticine, respectively. In contrast, no toxicity to these cancer cells was detectable for 7-hydroxyellipticine. The nuclease P1 version of the <sup>32</sup>P-postlabeling assay yielded a pattern of ellipticine-DNA adducts with two major and one minor adducts in MCF-7 cells, similar to the pattern of adducts detected in DNA reacted with ellipticine and the reconstituted cytochrome P450 enzyme system <i>in vitro</i> and in DNA <i>in vivo</i>. The identity of two major adducts formed in DNA of MCF-7 cells with those formed by cytochrome P450-mediated ellipticine activation <i>in vitro</i> was confirmed by HPLC of the isolated adducts. 9-Hydroxyellipticine was also capable of inducing DNA adducts in MCF-7 cells, but to a lesser extent. In addition, the adducts generated by 9-hydroxyellipticine were different from those generated by ellipticine. Negligible levels of DNA adducts were detectable in DNA of MCF-7 cells exposed to 7-hydroxyellipticine. The results presented here are the first report showing the formation of covalent DNA adducts with ellipticine in human breast cancer cells in culture, and suggest the formation of covalent DNA adducts as a new mode of antitumor action of ellipticine in breast cancer. <p>

Title:DNA Adduct Formation by the Anticancer Drug Ellipticine and Its Hydroxy Derivatives in Human Breast Adenocarcinoma MCF-7 Cells
Creators:
Bořek-Dohalská, Lucie
Frei, Eva
Stiborová, Marie
Uncontrolled Keywords:Anticancer drug, DNA adducts, Human cytochrome P450, Human breast cancer MCF-7 cells, Ellipticine, Antineoplastic activity, Activation, Cytotoxicity, <sup>32</sup>P-Postlabeling
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:69
Number:3
Page Range:pp. 603-615
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc20040603UNSPECIFIED
ID Code:2231
Item Type:Article
Deposited On:06 Feb 2009 17:16
Last Modified:06 Feb 2009 16:16

Citation

Bořek-Dohalská, Lucie; Frei, Eva; Stiborová, Marie (2004) DNA Adduct Formation by the Anticancer Drug Ellipticine and Its Hydroxy Derivatives in Human Breast Adenocarcinoma MCF-7 Cells. Collection of Czechoslovak Chemical Communications, 69 (3). pp. 603-615. ISSN 0010-0765

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