Effects of a phytoestrogen-containing soy extract on the growth-inhibitory activity of ICI 182 780 in an experimental model of estrogen-dependent breast cancer.
The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogen-dependent breast cancer.
Gallo
Daniela
D
Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
Mantuano
Elisabetta
E
Fabrizi
Manuela
M
Ferlini
Cristiano
C
Mozzetti
Simona
S
De Stefano
Ilaria
I
Scambia
Giovanni
G
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D048789:Phytoestrogens / Q000032:analysis / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D048789:Phytoestrogens; D010936:Plant Extracts; D012333:RNA, Messenger; D019700:Thrombospondin 1; D000077267:Fulvestrant; D004958:Estradiol; D007610:Kallikreins; C491223:Prss18 protein, mouse