Antitumor mechanism of action of a cyclopropyl antiestrogen (compound 7b) on human breast cancer cells in culture |
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Authors: | P T Jain J T Pento Robert A Magarian |
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Institution: | (1) Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall, Oklahoma City, OK 73190, USA, US |
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Abstract: | Cyclopropyl compound 7b (Z)-1,1-dichloro2-4-2-(dimethylamino)ethoxy] phenyl]-2-(4-methoxy-phenyl)-3-cyclopropane] has been shown to be a pure antiestrogen
in mouse uterine tissue. Antitumor activity was examined by evaluating the influence of 7b on the proliferation, estrogen
receptor (ER) affinity and cell-surface morphology of ER-positive and ER-negative human breast cancer cells in culture. The
antiproliferative potency of 7b was found to be equal to tamoxifen in ER-positive MCF-7 human breast cancer cells. Further,
the antiproliferative activities of 7b and tamoxifen were reversed by coadministration of estradiol. Accordingly, the antiproliferative
activity of compound 7b appears to be estrogen-mediated since it did not influence the growth of either ER-negative MDA-MB-231
human breast cells or A-549 human lung cancer cells in culture. An ER-dependent mechanism of action is also supported by the
specific binding affinity of 7b for ER in MCF-7 cells. Further, a study of cell surface morphology using scanning electron
microscopy (SEM) revealed that 7b reduced the density and distribution of microvilli (MV) on MCF-7 cells, which was reversed
by coadministration of estradiol. Compound 7b did not alter the cell surface morphology of ER-negative MDA-MB-231 cells. In
conclusion, 7b inhibited the growth of ER-positive MCF-7 cells in an estradiol-reversible manner, and had no effect on either
ER-negative MDA-MB-231 cells or A-549 lung cancer cells. The results of this study confirm an antiestrogenic mechanism of
action for 7b as previously observed in vivo and suggest that 7b would be effective in the treatment of estrogen-dependent
breast cancer or as a prophylactic treatment for women with a high risk of breast cancer development.
Received: 6 January 1995/Accepted: 9 October 1995 |
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Keywords: | Cyclopropyl antiestrogen Anticancer drug Human breast cancer |
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