Robinson S P, Jordan V C
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Cancer Res. 1989 Apr 1;49(7):1758-62.
The antiestrogen toremifene has been used to study the growth control of hormone-dependent (MCF-7), -independent (MDA-MB-231), or mixed tumor cell populations in athymic mice. Maximal MCF-7 tumor growth was produced in ovariectomized athymic mice by circulating estradiol levels of approximately 200 pg/ml (produced by 0.5-cm silastic capsules implanted s.c.). The antiestrogen toremifene (77 +/- 4 micrograms/day from a 2-cm silastic capsule) inhibited estradiol (0.5-cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist on the mouse uterus. The growth of hormone-independent MDA-MB-231 breast tumors implanted in athymic mice was not influenced by either estradiol (0.5-cm capsule) or toremifene (2-cm capsule) when administered alone or in combination. Furthermore, even very large doses of toremifene (5 mg/day p.o.) did not alter the rate of MDA-MB-231 tumor growth. Mixtures of MCF-7 and MDA-MB-231 cells in 9:1 and 99:1 ratios inoculated into athymic mice produced tumors which grew in the absence of estradiol but responded to estradiol supplementation (0.5-cm capsule) with a more rapid rate of tumor growth. Tumors grown from inoculated MCF-7:MDA-MB-231 cells (99:1 ratio) in the presence of estradiol had estrogen receptor levels of 33.2 +/- 9.2 fmol/mg of protein at Day 44 compared to 84.8 +/- 4.8 fmol/mg of protein in pure MCF-7 tumors. Toremifene (2-cm capsule) treatment inhibited the estrogen stimulation of these mixed tumors (99:1 starting ratio) to that of toremifene alone. However, toremifene-alone treatment produced a more rapid rate of tumor growth than control or tumors grown from irradiated MCF-7 cells mixed with viable MDA-MB-231 cells. Increasing the ratio of MCF-7:MDA-MB-231 cells (999:1) initially inoculated resulted in tumors which developed less rapidly than the lower ratio (99:1). Toremifene (2-cm capsule) again produced partial inhibition of 17 beta-estradiol-stimulated tumor growth while increasing tumor growth above control when the antiestrogen was administered alone. These results demonstrate that toremifene is effective in inhibiting estrogen stimulation of hormone-dependent tumors and partially successful at controlling mixed hormone-dependent/independent tumors; however, the antiestrogen cannot control the growth of a hormone-independent tumor in this model.
抗雌激素药物托瑞米芬已被用于研究无胸腺小鼠中激素依赖性（MCF - 7）、激素非依赖性（MDA - MB - 231）或混合肿瘤细胞群体的生长控制。在去卵巢的无胸腺小鼠中，循环雌二醇水平约为200 pg/ml（由皮下植入0.5 cm硅橡胶胶囊产生）时，MCF - 7肿瘤生长达到最大。抗雌激素药物托瑞米芬（来自2 cm硅橡胶胶囊，剂量为77±4微克/天）可抑制雌二醇（0.5 cm胶囊）刺激的生长达70%以上。单独使用托瑞米芬治疗的小鼠未观察到肿瘤生长，尽管托瑞米芬对小鼠子宫有较弱的部分激动作用。单独或联合给予雌二醇（0.5 cm胶囊）或托瑞米芬（2 cm胶囊）时，植入无胸腺小鼠的激素非依赖性MDA - MB - 231乳腺肿瘤的生长均未受到影响。此外，即使给予非常大剂量的托瑞米芬（口服5 mg/天）也未改变MDA - MB - 231肿瘤的生长速度。以9:1和99:1比例接种到无胸腺小鼠体内的MCF - 7和MDA - MB - 231细胞混合物产生的肿瘤，在无雌二醇的情况下生长，但补充雌二醇（0.5 cm胶囊）后肿瘤生长速度加快。在第44天时，在存在雌二醇的情况下，接种的MCF - 7:MDA - MB - 231细胞（99:1比例）产生的肿瘤的雌激素受体水平为33.2±9.2 fmol/mg蛋白质，而纯MCF - 7肿瘤中的雌激素受体水平为84.8±4.8 fmol/mg蛋白质。托瑞米芬（2 cm胶囊）治疗可将这些混合肿瘤（起始比例为99:1）的雌激素刺激抑制到单独使用托瑞米芬时的水平。然而，单独使用托瑞米芬治疗产生的肿瘤生长速度比对照或由照射过的MCF - 7细胞与活的MDA - MB - 231细胞混合产生的肿瘤更快。最初接种时增加MCF - 7:MDA - MB - 231细胞的比例（999:1）会导致肿瘤发展速度比低比例（99:1）时更慢。托瑞米芬（2 cm胶囊）再次部分抑制了17β - 雌二醇刺激的肿瘤生长，而单独给予抗雌激素时肿瘤生长速度高于对照。这些结果表明，托瑞米芬可有效抑制雌激素对激素依赖性肿瘤的刺激，并在控制混合激素依赖性/非依赖性肿瘤方面部分成功；然而，在该模型中，抗雌激素无法控制激素非依赖性肿瘤的生长。
