Yonou Hiroyuki, Ochiai Atsushi, Ashimine Satoshi, Maeda Hiroyuki, Horiguchi Yutaka, Yoshioka Kunihiko, Ogawa Yoshihide, Hatano Tadashi, Tachibana Masaaki
Department of Urology, Tokyo Medical University, Tokyo, Japan.
Prostate. 2007 Jun 15;67(9):999-1009. doi: 10.1002/pros.20592.
In men, prostate cancer frequently metastasizes to the bones, where it forms osteoblastic lesions with an osteolytic element that cause pain. However, the role of osteoclastogenesis in bone metastasis of human prostate cancer is unknown. Bisphosphonates are already known to be beneficical for treating osteolytic bone metastases, so we employed a model of osteoblastic bone tumor of human prostate cancer to investigate whether a new bisphosphonate (YM529: minodronate) could inhibit both the formation of bone tumors and the progression of established osteoblastic tumors.
Human prostate cancer cells (LNCaP) were injected into adult human bone implants in nonobese diabetic/severe combined immunodeficient mice, after which osteoblastic bone tumors developed. YM529 (1 microg/day) was administered subcutaneously every day for 2 weeks, starting either immediately or 2 weeks after implantation of the tumor cells, and the mice were sacrificed at 4 weeks after implantation. The bone tumors were examined histologically and the number of tartrate-resistant acid phosphatase-stained osteoclasts in each tumor focus was counted.
Histomorphometric analysis revealed that YM529 markedly inhibited both the formation of bone tumors and the progression of established tumors, as well as markedly reducing the number of osteoclasts.
YM529 reduced the tumor burden in bone by inhibiting both the formation of new lesions and the progression of existing tumors, suggesting that osteoclasts are involved in the formation of bone tumors by prostate cancer. Treatment with this bisphosphonate may potentially be beneficial for patients with bone metastases of prostate cancer.
在男性中，前列腺癌常转移至骨骼，在那里形成具有溶骨成分的成骨病变并导致疼痛。然而，破骨细胞生成在人类前列腺癌骨转移中的作用尚不清楚。双膦酸盐已被证实对治疗溶骨性骨转移有益，因此我们采用人类前列腺癌成骨骨肿瘤模型来研究一种新型双膦酸盐（YM529：米诺膦酸）是否能抑制骨肿瘤的形成以及已形成的成骨肿瘤的进展。
将人类前列腺癌细胞（LNCaP）注射到非肥胖糖尿病/严重联合免疫缺陷小鼠的成人骨植入物中，随后形成成骨骨肿瘤。从肿瘤细胞植入后立即开始或植入后2周开始，每天皮下注射YM529（1微克/天），持续2周，在植入后4周处死小鼠。对骨肿瘤进行组织学检查，并对每个肿瘤灶中抗酒石酸酸性磷酸酶染色的破骨细胞数量进行计数。
组织形态计量学分析显示，YM529显著抑制骨肿瘤的形成和已形成肿瘤的进展，同时显著减少破骨细胞数量。
YM529通过抑制新病变的形成和现有肿瘤的进展降低了骨中的肿瘤负荷，提示破骨细胞参与前列腺癌骨肿瘤的形成。用这种双膦酸盐治疗可能对前列腺癌骨转移患者有益。
