Lu Q, Liu Y, Long B J, Grigoryev D, Gimbel M, Brodie A
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201, USA.
Breast Cancer Res Treat. 1999 Sep;57(2):183-92. doi: 10.1023/a:1006225601046.
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.
我们之前已在裸鼠中建立了一种绝经后激素依赖性乳腺癌模型，该模型对抗雌激素和芳香化酶抑制剂均有反应。在这个模型中，转染了芳香化酶基因的MCF-7人乳腺癌细胞（MCF-7CA）能合成足够的雌激素，从而在去卵巢的裸鼠体内形成肿瘤。在本研究中，我们使用这种肿瘤内芳香化酶模型来研究新型非甾体芳香化酶抑制剂来曲唑（CGS 20,267）和阿那曲唑（ZD 1033）以及抗雌激素他莫昔芬（ICI 47,474）和氟维司群（ICI 182,780）对肿瘤生长的影响。此外，我们还确定了抑制雌激素合成与抑制雌激素作用相结合是否在控制乳腺肿瘤生长方面更有效。我们的研究结果表明，芳香化酶抑制剂阿那曲唑和来曲唑，以及新型纯抗雌激素氟维司群，在该小鼠模型中具有强大的抗肿瘤作用。在用乳腺肿瘤小鼠进行治疗时，来曲唑在抑制肿瘤生长方面比阿那曲唑更有效。这与这些抑制剂针对胎盘芳香化酶的Ki值以及细胞培养（MCF-7CA）中的IC50值一致，表明来曲唑作为芳香化酶抑制剂的效力更强。来曲唑的抗肿瘤作用也比他莫昔芬和氟维司群更强。来曲唑的抗肿瘤作用显著，以至于当来曲唑与抗雌激素联合使用时，很难检测到对肿瘤有任何额外的作用。然而，与单独使用芳香化酶抑制剂相比，阿那曲唑 + 他莫昔芬以及阿那曲唑 + 氟维司群的联合治疗也没有提高疗效。此外，联合使用两种抗雌激素并不比单独使用氟维司群更有效地抑制肿瘤生长。我们的结果表明，与单独使用芳香化酶抑制剂相比，芳香化酶抑制剂与他莫昔芬或氟维司群联合治疗在阻断雌激素对肿瘤生长的刺激方面并没有更有效。
