A Rationally Designed Genotoxin that Selectively Destroys Estrogen Receptor-Positive Breast Cancer Cells

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• 作者：Kaushik Mitra ; John C. Marquis ; Shawn M. Hillier ; Peter T. Rye ; Beatriz Zayas ; Annie S. Lee ; John M. Essigmann ; and Robert G. Croy
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：March 6, 2002
• 年：2002
• 卷：124
• 期：9
• 页码：1862 - 1863
• 全文大小：43K
• 年卷期：v.124,no.9(March 6, 2002)
• ISSN：1520-5126

文摘

We describe a novel strategy to increase the selective toxicity of genotoxic compounds. The strategy involves the synthesis of bifunctional molecules capable of forming DNA adducts that have high affinity for specific proteins in target cells. It is proposed that the association of such proteins with damaged sites in DNA can compromise protein function and/or DNA repair resulting in increased toxicity. We describe the synthesis of a bifunctional compound consisting of an aniline mustard linked to the 7 position of estradiol. This novel compound can form covalent DNA adducts that have high affinity for the estrogen receptor. Breast cancer cells that express high levels of the estrogen receptor showed increased sensitivity to the cytotoxic effects of the new compound.