title: A rationally designed genotoxin that selectively destroys estrogen receptor-positive breast cancer cells.
abstract: 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 7alpha 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.
authors.affiliation: Department of Chemistry and Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mitra
authors.forename: John C
authors.initials: JC
authors.lastname: Marquis
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Peter T
authors.initials: PT
authors.lastname: Rye
authors.forename: Beatriz
authors.initials: B
authors.lastname: Zayas
authors.forename: Annie S
authors.initials: AS
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Essigmann
authors.forename: Robert G
authors.initials: RG
authors.lastname: Croy
mesh_terms: D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D015195:Drug Design; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D011960:Receptors, Estrogen; D004958:Estradiol; D000816:Aniline Mustard