The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer.
We have previously established a model for postmenopausal, hormone-dependent breast cancer in nude mice which is responsive to both antiestrogens and aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to form tumors in ovariectomized nude mice. In the present study we used this intratumoral aromatase model to investigate the effects on tumor growth of the new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD 1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780). Furthermore, we determined whether the inhibition of estrogen synthesis together with inhibition of estrogen action would be more effective in controlling breast tumor growth. The results of our studies indicate that the aromatase inhibitors anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have potent antitumor effects in the mouse model. In the treatment of mice with mammary tumors, letrozole was more effective in suppressing tumor growth than anastrozole. This was consistent with the Ki values of these inhibitors against placental aromatase and the IC50 values in cell culture (MCF-7CA), which indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole also had greater antitumor effects than tamoxifen and faslodex. The antitumor effect of letrozole was substantial, making it difficult to detect any additional effect on the tumors when letrozole was combined with the antiestrogens. However, the combined treatment of anastrozole + tamoxifen and anastrozole + faslodex also did not increase efficacy compared to the aromatase inhibitor alone. In addition, combining the two antiestrogens did not suppress tumor growth more effectively than faslodex alone. Our results show that treatment with the combinations of aromatase inhibitors with either tamoxifen or faslodex are not more effective in blocking estrogen stimulation of tumor growth than the aromatase inhibitors alone.
Lu
Q
Q
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201, USA.
Liu
Y
Y
Long
B J
BJ
Grigoryev
D
D
Gimbel
M
M
Brodie
A
A
D000704:Analysis of Variance; D000077384:Anastrozole; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; 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 / Q000008:administration & dosage / Q000494:pharmacology; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase