title: Exploration of the therapeutic potential of the antiestrogen RU 58668 in breast cancer treatment.
abstract: The recently described pure antiestrogen RU 58668 displayed potent antiproliferative activities in vitro on several ER+ human mammary cell lines, stimulated either by estradiol or by endogenous or exogenous growth factors. Moreover, when administered to nude mice it proved to be the only antiestrogen to induce regression (at least 10 weeks) of estradiol-stimulated MCF-7 tumors, whereas tamoxifen only stabilized the tumor volume for 4 to 8 weeks. So the first purpose of this work was to study the effect of RU 58668 for 6 months and to evaluate its activity on tumors which escaped from the tamoxifen treatment. On the other hand, we looked for its effect on models more related to frequently described clinical observations, such as the overexpression of an oncogene or the implication of autocrine or paracrine growth factors. Long-term studies of RU 58668 on the estradiol-stimulated MCF-7 model showed that this compound induced a shrinking of tumor volumes for at least 25 weeks (3 to 6 times longer than the stabilization induced by tamoxifen) and was able to reduce the volume of tumors which escaped from, or even were stimulated by, tamoxifen. On models of spontaneously growing tumors, where the overexpression of an oncogene or the production of growth factors was involved, RU 58668 induced the same tumor shrinking that was previously observed on estradiol- or tamoxifen-stimulated models. Finally, when MCF-7 cells were injected in the uteri, a spontaneous tumor take was observed (in about 80-90% of the animals), leading to a more than twofold increase in uterus weight. This growth is largely stimulated by estradiol and tamoxifen. On this model, histological examination showed that only 30% of the animals receiving RU 58668 displayed tumoral microfoci. These studies suggest that RU 58668 may be used for the treatment of ER+ patients which are primarily resistant to or which escaped from tamoxifen treatment. Its preventive activity on tumor take also suggests its use as an adjuvant to prevent the development of metastases.
authors.affiliation: Department of Endocrinology, Roussel Uclaf, Romainville, France.
authors.forename: P
authors.initials: P
authors.lastname: Van de Velde
authors.forename: F
authors.initials: F
authors.lastname: Nique
authors.forename: J
authors.initials: J
authors.lastname: Brémaud
authors.forename: M C
authors.initials: MC
authors.lastname: Hameau
authors.forename: D
authors.initials: D
authors.lastname: Philibert
authors.forename: G
authors.initials: G
authors.lastname: Teutsch
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use; D014162:Transfection; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic; D014407:Tumor Cells, Cultured; D014599:Uterus; D005466:Fluorocarbons
chemical_list: D004958:Estradiol; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C086511:RU 58668; D005466:Fluorocarbons