Sasaki A, Boyce B F, Story B, Wright K R, Chapman M, Boyce R, Mundy G R, Yoneda T
University of Texas Health Science Center at San Antonio, Department of Medicine 78284-7877, USA.
Cancer Res. 1995 Aug 15;55(16):3551-7.
Human breast cancer frequently metastasizes to the skeleton to cause osteolysis and subsequent pain, pathological fracture, and hypercalcemia. Because bone continuously releases growth factors stored in bone matrix by bone resorption during physiological remodeling and, thus, possibly provides a favorable microenvironment for metastatic breast cancer cells to proliferate, inhibitors of bone resorption used either prophylactically or in patients with established disease, therefore, would seem likely to be useful adjuvant therapy in patients with breast cancer. However, the parameters for monitoring progressive osteolytic bone disease in humans are imprecise. We examined the effects of the third generation bisphosphonate, risedronate, which is a specific inhibitor of osteoclastic bone resorption, in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-231 leads to osteolytic bone metastases. Risedronate (4 micrograms/animal/day) was given s.c. to animals (a) after radiologically small but defined osteolytic metastases were observed; (b) simultaneously with MDA-231 cell inoculation through the entire experimental period; or (c) by short-term prophylactic administration before inoculation of MDA-231 cells. In all experiments, risedronate either slowed progression or inhibited the development of bone metastases assessed radiographically. Furthermore, mice treated continuously with risedronate showed significantly longer survival than did control mice. Histomorphometrical analysis revealed that osteoclast numbers were diminished at metastatic tumor sites. Unexpectedly, there was also a marked decrease in tumor burden in bone in risedronate-treated animals. In contrast, the growth of metastatic breast cancer in soft tissues surrounding bones was not affected by risedronate. Moreover, risedronate had no effects on the local growth of s.c. implanted MDA-231 breast cancers in nude mice or on MDA-231 cell proliferation in culture. These data demonstrate that risedronate decreases metastatic MDA-231 breast cancer burden selectively in bone, as well as suppresses progression of established osteolytic lesions and prevents the development of new osteolytic lesions; thus, the data suggest that inhibition of osteoclastic bone resorption may be a useful adjunctive therapy for the treatment of cancers that have colonized in bone.
人类乳腺癌常转移至骨骼，导致骨质溶解以及随后出现疼痛、病理性骨折和高钙血症。由于在生理重塑过程中，骨骼通过骨吸收持续释放存储在骨基质中的生长因子，因此可能为转移性乳腺癌细胞的增殖提供有利的微环境，所以，预防性使用或用于已确诊疾病患者的骨吸收抑制剂，似乎有可能成为乳腺癌患者有用的辅助治疗方法。然而，用于监测人类进行性溶骨性骨病的参数并不精确。我们在裸鼠骨转移模型中研究了第三代双膦酸盐利塞膦酸盐（一种破骨细胞骨吸收的特异性抑制剂）的作用，在该模型中，经心内注射人乳腺癌细胞系MDA - 231会导致溶骨性骨转移。利塞膦酸盐（4微克/动物/天）通过皮下注射给予动物：(a) 在经放射学检查发现虽小但已明确的溶骨性转移灶之后；(b) 在整个实验期间与MDA - 231细胞接种同时进行；或(c) 在接种MDA - 231细胞之前进行短期预防性给药。在所有实验中，利塞膦酸盐要么减缓了骨转移的进展，要么抑制了经放射学评估的骨转移的发展。此外，持续接受利塞膦酸盐治疗的小鼠的存活时间明显长于对照小鼠。组织形态计量学分析显示，转移瘤部位的破骨细胞数量减少。出乎意料的是，接受利塞膦酸盐治疗的动物骨内的肿瘤负荷也显著降低。相比之下，骨骼周围软组织中转移性乳腺癌的生长不受利塞膦酸盐的影响。此外，利塞膦酸盐对裸鼠皮下植入的MDA - 231乳腺癌的局部生长或对培养中的MDA - 231细胞增殖均无影响。这些数据表明，利塞膦酸盐能选择性降低骨内转移性MDA - 231乳腺癌的负荷，同时抑制已形成的溶骨性病变的进展并防止新的溶骨性病变的形成；因此，数据表明抑制破骨细胞骨吸收可能是治疗已在骨内定植的癌症的一种有用的辅助治疗方法。
