Yoneda T, Michigami T, Yi B, Williams P J, Niewolna M, Hiraga T
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7877, USA.
Cancer. 2000 Jun 15;88(12 Suppl):2979-88. doi: 10.1002/1097-0142(20000615)88:12+<2979::aid-cncr13>3.0.co;2-u.
Bone, which abundantly stores a variety of growth factors, provides a fertile soil for cancer cells to develop metastases by supplying these growth factors as a consequence of osteoclastic bone resorption. Accordingly, suppression of osteoclast activity is a primary approach to inhibit bone metastasis, and bisphosphonate (BP), a specific inhibitor of osteoclasts, has been widely used for the treatment of bone metastases in cancer patients. To obtain further insights into the therapeutic usefulness of BP, the authors studied the effects of BP on bone and visceral metastases in animal models of metastasis.
The authors used two animal models of breast carcinoma metastasis that they had developed in their laboratory over the last several years. One model uses female young nude mice in which inoculation of the MDA-MB-231 or MCF-7 human breast carcinoma cells into the left cardiac ventricle selectively develops osteolytic or osteosclerotic bone metastases, respectively. Another model uses syngeneic female mice (Balb/c) in which orthotopic inoculation of the 4T1 murine mammary carcinoma cells develops metastases in bone and visceral organs including lung, liver, and kidney.
BP inhibited the development and progression of osteolytic bone metastases of MDA-MB-231 breast carcinoma through increased apoptosis in osteoclasts and breast carcinoma cells colonized in bone. In a preventative administration, however, BP alone increased the metastases to visceral organs with profound inhibition of bone metastases. However, combination of BP with anticancer agents such as uracil and tegafur or doxorubicin suppressed the metastases not only in bone but also visceral organs and prolonged the survival in 4T1 mammary tumor-bearing animals. Of interest, inhibition of early osteolysis by BP inhibited the subsequent development of osteosclerotic bone metastases of MCF-7 breast carcinoma.
These results suggest that BP has beneficial effects on bone metastasis of breast carcinoma and is more effective when combined with anticancer agents. They also suggest that the animal models of bone metastasis described here allow us to design optimized regimen of BP administration for the treatment of breast carcinoma patients with bone and visceral metastases.
骨骼大量储存多种生长因子，破骨细胞介导的骨吸收会释放这些生长因子，从而为癌细胞发生转移提供了适宜的环境。因此，抑制破骨细胞活性是抑制骨转移的主要方法，双膦酸盐（BP）作为破骨细胞的特异性抑制剂，已广泛应用于癌症患者骨转移的治疗。为了进一步了解BP的治疗效果，作者研究了BP在转移动物模型中对骨转移和内脏转移的影响。
作者使用了他们在过去几年中建立的两种乳腺癌转移动物模型。一种模型使用雌性幼年裸鼠，将MDA-MB-231或MCF-7人乳腺癌细胞接种到左心室，分别选择性地形成溶骨性或骨硬化性骨转移。另一种模型使用同基因雌性小鼠（Balb/c），将4T1鼠乳腺癌细胞原位接种后，会在骨及包括肺、肝和肾在内的内脏器官发生转移。
BP通过增加骨中破骨细胞和乳腺癌细胞的凋亡，抑制MDA-MB-231乳腺癌溶骨性骨转移的发生和进展。然而，在预防性给药时，单独使用BP会增加内脏器官的转移，同时显著抑制骨转移。但是，BP与抗癌药物如尿嘧啶和替加氟或多柔比星联合使用时，不仅能抑制骨转移，还能抑制内脏器官转移，并延长4T1荷瘤动物的生存期。有趣的是，BP对早期骨溶解的抑制作用抑制了MCF-7乳腺癌随后骨硬化性骨转移的发生。
这些结果表明，BP对乳腺癌骨转移具有有益作用，与抗癌药物联合使用时效果更佳。它们还表明，本文所述的骨转移动物模型使我们能够设计出优化的BP给药方案，用于治疗伴有骨转移和内脏转移的乳腺癌患者。
