Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model.
The effects of aromatase inhibitors 4-hydroxyandrostenedione (4-OHA), CGS 16949A, and CGS 20267, and of the antiestrogen tamoxifen (TAM), were studied on the growth of human breast carcinoma in a nude mouse model. To simulate the postmenopausal breast cancer patient, tumors were formed from inoculates of MCF-7 cells transfected with the human aromatase gene to provide a source of non-ovarian estrogen in ovariectomized mice. Tumor growth was significantly inhibited by all treatments (P < 0.05). Greater reduction in growth occurred in mice treated with TAM combined with aromatase inhibitors than with TAM alone. Tumor progesterone receptor concentrations were unaltered by TAM treatment but were reduced by aromatase inhibitors. Progesterone receptor concentrations correlated with tumor growth. The greatest reduction occurred in tumors of CGS 20267-treated mice in which no progesterone receptors were detected. In the ovariectomized mice used in these studies, uterine weight was maintained by estrogen produced from the tumor. Uterine weight was reduced by aromatase inhibitors but not by TAM treatment. However, there was a significant increase in uterine weight in mice treated with the combination of TAM and 4-OHA. Thus, the agonist effect of TAM was evident when estrogen synthesis was inhibited. The results indicate that aromatase inhibitors have potent effects on mammary tumor growth but lack the estrogenic effects on the uterus observed with TAM. There appeared to be no significant benefit in combining TAM with 4-OHA over 4-OHA treatment alone.
Yue
W
W
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
Wang
J
J
Savinov
A
A
Brodie
A
A
D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D002455:Cell Division / Q000187:drug effects; D017316:Fadrozole / Q000494:pharmacology; D005260:Female; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000735:Androstenedione; D000077289:Letrozole; D017316:Fadrozole; C014594:formestane