Cicek Muzaffer, Iwaniec Urszula T, Goblirsch Michael J, Vrabel Anne, Ruan Ming, Clohisy Denis R, Turner Russell R, Oursler Merry Jo
Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Cancer Res. 2007 Nov 1;67(21):10106-11. doi: 10.1158/0008-5472.CAN-07-1362.
2-Methoxyestradiol (2ME(2)), a physiologic metabolite of 17beta-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME(2) also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME(2) could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME(2) (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME(2) inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME(2). In vitro, 2ME(2) repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME(2) could be an important new therapy in the arsenal to fight metastatic breast cancer.
2-甲氧基雌二醇（2ME₂）是17β-雌二醇（雌激素）的一种生理代谢产物，因其对内皮细胞和肿瘤细胞具有强大的生长抑制和促凋亡作用，已成为一种有前景的癌症治疗药物。2ME₂还能抑制破骨细胞分化并诱导成熟破骨细胞凋亡，且已在绝经后骨质疏松动物模型中显示出能有效抑制骨质流失。基于这些观察结果，我们研究了2ME₂是否能有效靶向骨转移、溶骨性肿瘤和软组织肿瘤。构建了一种稳定表达远红荧光蛋白的4T1小鼠转移性乳腺癌细胞系（4T1/Red），以可视化肿瘤发展和骨转移情况。在一项干预研究中，将4T1/Red细胞注入左股骨骨髓和乳腺垫。在后者的研究中，2ME₂（10、25和50毫克/千克/天）治疗在手术当天开始，并持续整个16天的研究期。监测肿瘤细胞生长和骨转移情况，并通过微型计算机断层扫描测定骨体积。2ME₂抑制软组织中的肿瘤生长、骨转移、骨溶解以及骨中的肿瘤生长，在50毫克/千克/天时效果最佳。此外，接受2ME₂治疗的小鼠中肿瘤诱导的骨溶解明显减少。在体外，2ME₂通过诱导破骨细胞前体以及成熟破骨细胞凋亡来减少破骨细胞数量。我们的数据支持这样的结论，即2ME₂可能成为对抗转移性乳腺癌的重要新疗法。
