title: A comparison of the antitumor activity of two triarylcyclopropyl antiestrogens (compounds 4d and 5c) on human breast cancer cells in culture.
abstract: Compound 4d ((E)- and (Z)-1,1-Dichloro-2-[4-(benzyloxy)-phenyl]2,3-bis(4-methoxyphenyl) cyclopropane) and compound 5c ((Z)-1,1-Dichloro-2-[4-(benzyloxy)-phenyl]- 2-(4-methoxyphenyl)-3-phenylcyclopropane) are two members of a novel series of triarylcyclopropyl compounds which have been shown to be pure antiestrogens. In the present study, the antiproliferative activity of 4d and 5c was examined on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells. Compound 4d inhibited the growth of MCF-7 cells in a dose-related manner over a concentration range of 10(-13) to 10(-5) M while compound 5c inhibited MCF-7 cell growth in a dose-related manner over a concentration range of 10(-9) to 10(-5) M. Further, neither compound altered the growth of MDA-MB-231 or A-549 cells. Co-administration of estradiol reversed the antiproliferative activity of 4d but not 5c on MCF-7 cells. Both compounds bound specifically to ER in MCF-7 cells; however, the relative binding activity of 4d was five times greater than estradiol and 5000 times greater than 5c. The influence of 4d and 5c on the cell surface morphology of MCF-7 and MDA-MB-231 cells was studied using scanning electron microscopy. Both compounds, at a concentration of 10(-6) M, reduced the density of microvilli on MCF-7 cells, which was reversed by co-administration of estradiol (10 (-8) M). These compounds did not alter the cell surface morphology of ER-negative MDA-MB-231 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Medicinal Chemistry and Pharmacodynamics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
authors.forename: P T
authors.initials: PT
authors.lastname: Jain
authors.forename: J T
authors.initials: JT
authors.lastname: Pento
authors.forename: R A
authors.initials: RA
authors.lastname: Magarian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C090356:1,1-dichloro-2-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)-3-phenylcyclopropane; D000970:Antineoplastic Agents; D003521:Cyclopropanes; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C088187:1,1-dichloro-2-(4-benzyloxyphenyl)-2,3-bis(4-methoxyphenyl)cyclopropane; D004958:Estradiol