Lee Yu-Po, Schwarz Edward M, Davies Mark, Jo Mark, Gates Jeffrey, Zhang Xuguang, Wu Jing, Lieberman Jay R
Department of Orthopaedic Surgery, David Geffen School of Medicine, Los Angeles, California 90095, USA.
Cancer Res. 2002 Oct 1;62(19):5564-70.
Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It has been hypothesized that osteoclastic bone resorption is a critical component before the development of these osteoblastic lesions in bone. This observation has led researchers to test agents that inhibit osteoclastic activity to prevent or halt the formation of metastatic prostate cancer lesions in bone. Bisphosphonates inhibit osteoclast activity, and previous studies showed that they have the ability to reduce the osteolytic bone resorption associated with multiple myeloma and breast cancer. The objective of this study was to evaluate the efficacy of zoledronate in limiting the formation and/or progression of osteoblastic lesions produced by the injection of known prostate cancer cells (LAPC-9 and PC-3 cells) into the tibia of SCID mice. The mice were treated with either 30- micro g or 150- micro g doses of zoledronate before tumor implantation (pretreatment group), or at weekly intervals after tumor implantation (weekly treatment group), or weekly starting one month after tumor implantation (delayed-treatment group). The zoledronate was very effective in limiting the formation of osteolytic lesions in PC-3 implanted tibias by inhibiting osteoclast activity. Radiographic and histological analysis at weekly intervals revealed that osteolytic lesions developed in the control tibias by 2 weeks, and there was complete destruction of the cortical bone in much of the proximal tibias by 4 weeks. In the treatment groups, there was minimal cortical destruction noted in the weekly treatment groups at both doses, whereas mild cortical erosion was evident in the pretreatment groups, with more cortical destruction noted in the 30- micro g group compared with the 150- micro g group. Tartrate-resistant acid phosphatase (TRAP) staining showed that zoledronate decreased osteoclastic numbers and that there was a dose-dependent response. In tibias implanted with the LAPC-9 cells, the zoledronate was not effective in halting the formation of the osteoblastic lesions. Radiographic and histological analysis revealed that osteoblastic lesions either had formed or were developing in 18 of 18 of the control tibias and 36 of 36 of the treated tibias at 8 weeks regardless of dose or treatment schedule. Furthermore, TRAP staining demonstrated that osteoblastic lesions had formed in the LAPC-9 tibias under conditions in which osteoclast numbers were significantly reduced. These results suggest that osteoclast activity may not be critical for the development of osteoblastic lesions associated with prostate tumor cells. Hence, bisphosphonates may not be ideal agents to prevent the formation of osteoblastic lesions associated with prostate cancer metastases to bone.
前列腺腺癌与骨中形成成骨性转移灶有关。据推测，破骨细胞介导的骨吸收是这些骨中成骨性病变发生之前的一个关键环节。这一观察结果促使研究人员测试抑制破骨细胞活性的药物，以预防或阻止前列腺癌骨转移灶的形成。双膦酸盐可抑制破骨细胞活性，先前的研究表明它们有能力减少与多发性骨髓瘤和乳腺癌相关的溶骨性骨吸收。本研究的目的是评估唑来膦酸在限制通过将已知前列腺癌细胞（LAPC - 9和PC - 3细胞）注射到SCID小鼠胫骨中所产生的成骨性病变的形成和/或进展方面的疗效。在肿瘤植入前（预处理组），或在肿瘤植入后每周一次（每周治疗组），或在肿瘤植入后一个月开始每周一次（延迟治疗组），分别用30μg或150μg剂量的唑来膦酸治疗小鼠。唑来膦酸通过抑制破骨细胞活性，在限制PC - 3植入胫骨中溶骨性病变的形成方面非常有效。每周进行的影像学和组织学分析显示，对照胫骨在2周时出现溶骨性病变，到4周时大部分近端胫骨的皮质骨完全破坏。在治疗组中，两个剂量的每周治疗组皮质破坏最小，而预处理组有轻度皮质侵蚀，30μg组比150μg组的皮质破坏更明显。抗酒石酸酸性磷酸酶（TRAP）染色显示唑来膦酸减少了破骨细胞数量，且存在剂量依赖性反应。在植入LAPC - 9细胞的胫骨中，唑来膦酸在阻止成骨性病变的形成方面无效。影像学和组织学分析显示，无论剂量或治疗方案如何，在8周时，18只对照胫骨中的18只以及36只治疗胫骨中的36只都已形成或正在形成成骨性病变。此外，TRAP染色表明，在破骨细胞数量显著减少的情况下，LAPC - 9胫骨中仍形成了成骨性病变。这些结果表明，破骨细胞活性对于与前列腺肿瘤细胞相关的成骨性病变的发生可能并非关键因素。因此，双膦酸盐可能不是预防与前列腺癌骨转移相关的成骨性病变形成的理想药物。
