11 beta-Amidoalkoxyphenyl estradiols, a new series of pure antiestrogens.
11 beta-Amidoalkoxyphenyl estradiols, a series of new antiestrogens, have been prepared and compared with tamoxifen (TAM) and 4-hydroxytamoxifen (OH-TAM). In vitro, these compounds were up to 20 times as active as OH-TAM on estradiol (E2)-stimulated MCF-7 cells. Unlike TAM or OH-TAM which were inactive, they displayed potent growth inhibitory effects on MCF-7 cells stimulated by a cocktail of epidermal growth factor and platelet derived growth factor. One of the most active compounds, 5e, was tested in vivo for its antiuterotrophic and antitumoral activities: it proved to be fully antiuterotrophic at 3 mg/kg subcutaneously in mice while being devoid of any uterotrophic activity. It inhibited the E2-induced growth of MCF-7 tumors implanted in nude mice and prevented the partial agonistic activity of TAM on MCF-7 tumor growth in ovariectomized mice. Moreover, on MCF-7 variant tumors, 5e, unlike TAM, did not display any proliferative activity, but inhibited the TAM-induced growth. Overall, these results show that this new series of compounds displays an improved activity profile compared with that of TAM, on tests relevant to human breast cancer treatment.
Nique
F
F
Centre de Recherches Roussel UCLAF, France.
Van de Velde
P
P
Brémaud
J
J
Hardy
M
M
Philibert
D
D
Teutsch
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D010982:Platelet-Derived Growth Factor; D013629:Tamoxifen; C088767:N-butyl-2-(5-(4-(3,17-dihydroxyestra-1,3,5(10)-trien-11-yl)phenoxy)pentylthio)-N-methylacetamide; C016601:afimoxifene; D004958:Estradiol; D004815:Epidermal Growth Factor