Jelovac Danijela, Macedo Luciana, Goloubeva Olga G, Handratta Venkatesh, Brodie Angela M H
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Cancer Res. 2005 Jun 15;65(12):5439-44. doi: 10.1158/0008-5472.CAN-04-2782.
Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 microg/d; n = 18), or letrozole (10 microg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 microg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 microg/d; n = 6), tamoxifen (100 microg/d; n = 6), or remained on letrozole treatment (10 microg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 microg/d).
使用抗雌激素药物阻断雌激素受体以及使用芳香化酶抑制剂阻断雌激素合成是目前用于降低绝经后雌激素受体阳性乳腺癌患者雌激素作用的两种策略。为优化这些治疗策略，我们研究了将纯抗雌激素药物氟维司群与非甾体芳香化酶抑制剂来曲唑联合使用是否能延缓肿瘤进展。这些研究是在切除卵巢的无胸腺小鼠身上进行的，这些小鼠携带稳定转染了芳香化酶基因（MCF-7Ca）的雌激素受体阳性人乳腺癌细胞肿瘤。将肿瘤体积相当的小鼠分组，每天皮下注射溶媒（对照组；n = 6）、氟维司群（1 mg/天；n = 7）、来曲唑（10 μg/天；n = 18）或来曲唑（10 μg/天）加氟维司群（1 mg/天；n = 5）。与对照组相比，所有治疗在抑制肿瘤生长方面均有效（P < 0.001）。氟维司群治疗组的肿瘤体积在10周内翻倍。来曲唑（10 μg/天）治疗19周后，此时肿瘤体积几乎翻倍，将小鼠（n = 18）分配接受二线治疗，分别给予来曲唑（100 μg/天；n = 6）、他莫昔芬（100 μg/天；n = 6），或继续接受来曲唑治疗（10 μg/天；n = 6）。然而，这些组的肿瘤体积继续增大。来曲唑加氟维司群联合治疗的动物肿瘤在29周的治疗过程中缩小了45%。因此，来曲唑加氟维司群联合治疗在抑制肿瘤生长方面比单独使用来曲唑或氟维司群，或与他莫昔芬或更高剂量来曲唑（100 μg/天）的序贯治疗更有效。
