Effects of a new synthetic vitamin D analogue, EB1089, on the oestrogen-responsive growth of human breast cancer cells.
The anti-proliferative effects of the novel vitamin D analogue, EB1089, were assessed in the hormone-dependent breast cancer cell line, MCF-7, in vitro. In the present study, EB1089 was shown to be at least an order of magnitude more potent at inhibiting MCF-7 cell proliferation than the native hormone, 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). Treatment of MCF-7 cell cultures with combinations of oestradiol and EB1089 ranging from 5 x 10(-11) M to 5 x 10(-9) M revealed the ability of EB1089 to suppress the mitogenic effects of oestradiol in these cells dose-dependently, as determined by [3H]thymidine incorporation and cell counts. EB1089 also exhibited a significant time- and dose-dependent decrease in MCF-7 oestrogen receptor (ER) concentration, as assessed by ligand binding assay. A fourfold reduction of ER levels by 5 x 10(-9) M EB1089 relative to control ER levels was observed, whilst 5 x 10(-9) M 1,25(OH)2D3 produced a significant but less dramatic decrease in ER levels. In addition, reduction of ER protein in EB1089-treated cell cultures was also demonstrated using an oestrogen receptor enzyme immunoassay. The interaction of EB1089 and anti-oestrogens on the oestradiol-stimulated growth of MCF-7 cells was investigated. The treatment of cell cultures with 5 x 10(-10) M EB1089 in combination with the pure anti-oestrogen, ICI 182,780 (5 x 10(-8) M), and in the presence of between 5 x 10(-10) M and 5 x 10(-9) M oestradiol, produced an augmented inhibition of MCF-7 cell proliferation compared with the actions of either compound alone.(ABSTRACT TRUNCATED AT 250 WORDS)
James
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Department of Clinical Biochemistry, St George's Hospital Medical School, London, UK.
Mackay
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Binderup
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Colston
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KW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D011960:Receptors, Estrogen / Q000032:analysis / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D002117:Calcitriol; C078903:seocalcitol