期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 103, 期 2, 页码 256-261出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2008.10.013
关键词
Pt(II)-estrogen anticancer drug; Estrogen receptor; Cytotoxic agent; Breast and ovarian cancers
资金
- National Institutes of Health [CA08661]
- Life Sciences Research Foundation
- National Science Foundation [DBI-9729592, CHE-9808061]
A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl-2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7 alpha-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17 beta-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17 beta-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl2 Was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231. (C) 2008 Elsevier Inc. All rights reserved.
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