Comparison between novel steroid-like and conventional nonsteroidal antioestrogens in inhibiting oestradiol- and IGF-I-induced proliferation of human breast cancer-derived cells.
1. This study has two specific aims: (a) to compare the antioestrogenic activity of two steroidal analogues of 17 beta-oestradiol, the 7 alpha-alkylamide, ICI 164,384 and the 7 alpha-alkylsulphinylamide, ICI 182,780, with that of the triphenylethylene-derived compound 4OH-tamoxifen on a pool of human breast cancer cell lines (HBCCL) with a range of hormonal responsiveness and acquired anti-oestrogen resistance and (b) to investigate the ability of such antioestrogens to modulate the potent breast carcinoma growth-stimulatory activity of the 'IGF-I system'. 2. For the chemosensitivity investigations we used a long-term colorimetric and the short-term thymidine incorporation assay; we analysed IGF-I in conditioned media by a radioimmunoassay, IGF-I mRNA in the cells by RT-PCR and molecular species of IGF-I-binding proteins, secreted in conditioned media, by Western ligand blot. IGF-I receptors were assayed on cell monolayers by binding studies and by Scatchard analysis, we calculated KD, Bmax and sites/cell. 3. Our results indicate that ICI 182,780 and ICI 164,384 are 1.5-5.5 fold more potent than 4OH-tamoxifen in inhibiting the basal proliferation of oestrogen-receptor positive (ER+) breast cancer cell lines. Moreover we demonstrate the capacity of ICI 182,780 and ICI 164,384 to reduce, in a time-dependent fashion, oestrogen- and/or IGF-I-stimulated growth of ER+cell lines, possibly by negatively interfering with an IGF-I-like material secretion and IGF-I-receptor number. 4. Our data provide the first evidence that, on ER+human breast carcinoma cell lines, steroidal antioestrogens inhibit cell growth and modulate the IGF-I mitogenic system. The mechanism of this latter effect has yet to be identified.
de Cupis
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A
Department of Experimental Pharmacology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Noonan
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D
Pirani
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P
Ferrera
A
A
Clerico
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L
Favoni
R E
RE
D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D004247:DNA / Q000096:biosynthesis; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008969:Molecular Sequence Data; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000096:biosynthesis; D013256:Steroids / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D013256:Steroids; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C051781:ICI 164384; D004247:DNA