Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice.
Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice.
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发表时间：
1995-08
期刊：
影响因子：
11.2
通讯作者：
Akira Sasaki;Brendan F. Boyce;B. Story;Kenneth R. Wright;Mark Chapman;Rogely Boyce;G. R. Mundy;Toshiyuki Yoneda
中科院分区：
文献类型：
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作者：
Akira Sasaki;Brendan F. Boyce;B. Story;Kenneth R. Wright;Mark Chapman;Rogely Boyce;G. R. Mundy;Toshiyuki Yoneda
人乳腺癌经常转移到骨骼，引起骨质溶解和随后的疼痛、病理性骨折和高钙血症。由于骨在生理重塑过程中通过骨吸收持续释放储存在骨基质中的生长因子，因此可能为转移性乳腺癌细胞增殖提供有利的微环境，因此，骨吸收抑制剂用于治疗或用于已确诊疾病的患者，似乎可能是乳腺癌患者的有用辅助治疗。然而，用于监测人类进行性溶骨性骨病的参数是不精确的。我们研究了第三代双膦酸盐利塞膦酸盐的作用，利塞膦酸盐是一种特异性骨吸收抑制剂，在裸鼠骨转移模型中，心内注射人乳腺癌细胞系MDA-231导致溶骨性骨转移。利塞膦酸盐（4微克/动物/天）皮下给药。（a）在观察到放射学上小但确定的溶骨性转移后;（B）在整个实验期间与MDA-231细胞接种同时;或（c）在接种MDA-231细胞前短期预防性给药。在所有实验中，利塞膦酸钠减缓进展或抑制骨转移的发展，通过放射学评估。此外，连续用利塞膦酸钠治疗的小鼠显示出比对照小鼠显著更长的存活时间。组织形态计量学分析显示，破骨细胞数量减少转移肿瘤部位。出乎意料的是，在利塞膦酸盐治疗的动物中，骨中的肿瘤负荷也显著降低。相反，转移性乳腺癌在骨周围软组织中的生长不受利塞膦酸钠的影响。利塞膦酸钠对皮下局部生长无影响。MDA-231乳腺癌裸鼠移植瘤或培养的MDA-231细胞增殖。这些数据表明，利塞膦酸盐选择性地降低骨中的转移性MDA-231乳腺癌负荷，以及抑制已建立的溶骨性病变的进展，并防止新的溶骨性病变的发展;因此，数据表明，抑制骨细胞骨吸收可能是一种有用的连续治疗，用于治疗已在骨中定植的癌症。
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.