Osborne C K, Hobbs K, Clark G M
Cancer Res. 1985 Feb;45(2):584-90.
Endocrine therapy with estrogen deprivation or with antiestrogens results in tumor regression in a subset of patients with advanced breast cancer. To better understand the mechanisms by which estrogens and antiestrogens modulate breast cancer growth in vivo, we have studied the effects of endocrine manipulation on the development and growth of tumors derived from cultured human breast cancer cells in the athymic nude mouse. MCF-7 breast cancer cells were inoculated into 6-week-old female BALB/c athymic nude mice. Tumor growth did not occur in ovariectomized mice. Cells remained viable, however, since estrogen supplementation more than 30 days later resulted in tumor formation. Minimal tumor growth was observed in intact female nude mice which have low circulating estrogen levels. Tumor development and growth in ovariectomized or intact mice supplemented with 17 beta-estradiol in the form of a s.c. pellet were dose dependent; growth rates increased with estrogen doses ranging from 0.01 to 0.5 mg. Antiestrogen treatment with either tamoxifen or LY156758 caused transient stimulation of tumor growth, followed by a prolonged stationary phase. Growth resumed with estrogen supplementation. Treatment of mice bearing established MCF-7 tumors with estrogen withdrawal (removal of estrogen pellet) resulted in cessation of tumor growth, but not in tumor regression. Growth inhibition was also observed with antiestrogens and was dose dependent. However, tumor regression did not occur, even in mice treated with high doses of tamoxifen (serum concentration of 1.0 microM) for as long as 60 days. Tumor growth was restored in these mice with estrogen replenishment. Tumor cells also remained viable histologically despite prolonged (1 month) estrogen deprivation or antiestrogen therapy, although the mitotic index was markedly reduced. Similar observations were made with mice inoculated with the hormone-responsive ZR75-1 human breast cancer cells, but not with hormone-independent MDA-231 cells which were not influenced by estrogen or antiestrogen treatment. In summary, development and growth of MCF-7 and ZR75-1 tumors in nude mice are estrogen dependent. Endocrine therapy by estrogen deprivation or antiestrogen treatment inhibits tumor cell proliferation in nude mice, but does not cause tumor regression or loss of cell viability.
雌激素剥夺或抗雌激素内分泌治疗可使一部分晚期乳腺癌患者的肿瘤消退。为了更好地理解雌激素和抗雌激素在体内调节乳腺癌生长的机制，我们研究了内分泌干预对无胸腺裸鼠体内源自培养人乳腺癌细胞的肿瘤发生和生长的影响。将MCF - 7乳腺癌细胞接种到6周龄雌性BALB/c无胸腺裸鼠体内。去卵巢小鼠未发生肿瘤生长。然而，细胞仍保持活力，因为30多天后补充雌激素会导致肿瘤形成。在循环雌激素水平低的完整雌性裸鼠中观察到最小程度的肿瘤生长。去卵巢或完整小鼠皮下植入含17β - 雌二醇的药丸后，肿瘤的发生和生长呈剂量依赖性；雌激素剂量在0.01至0.5毫克范围内，生长速率随剂量增加。用他莫昔芬或LY156758进行抗雌激素治疗会导致肿瘤生长短暂刺激，随后是长时间的静止期。补充雌激素后生长恢复。对已形成MCF - 7肿瘤的小鼠进行雌激素撤药（取出雌激素药丸）治疗会导致肿瘤生长停止，但不会使肿瘤消退。抗雌激素治疗也观察到生长抑制且呈剂量依赖性。然而，即使在用高剂量他莫昔芬（血清浓度为1.0微摩尔）治疗长达60天的小鼠中，肿瘤也未消退。补充雌激素后这些小鼠的肿瘤生长得以恢复。尽管长时间（1个月）雌激素剥夺或抗雌激素治疗，肿瘤细胞在组织学上仍保持活力，尽管有丝分裂指数明显降低。对接种激素反应性ZR75 - 1人乳腺癌细胞的小鼠也有类似观察结果，但对接种激素非依赖性MDA - 231细胞的小鼠没有类似结果，后者不受雌激素或抗雌激素治疗影响。总之，裸鼠体内MCF - 7和ZR75 - 1肿瘤的发生和生长依赖雌激素。通过雌激素剥夺或抗雌激素治疗的内分泌疗法可抑制裸鼠体内肿瘤细胞增殖，但不会导致肿瘤消退或细胞活力丧失。
