Effect of combination therapy with a novel bisphosphonate, minodronate (YM529), and docetaxel on a model of bone meta stasis by human transitional cell carcinoma
Effect of combination therapy with a novel bisphosphonate, minodronate (YM529), and docetaxel on a model of bone meta stasis by human transitional cell carcinoma
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DOI：
10.1158/1078-0432.ccr-05-1010
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发表时间：
2005-09-15
影响因子：
11.5
通讯作者：
Shuin, T
中科院分区：
文献类型：
--
作者：
Inoue, K;Karashima, T;Shuin, T
目的：移行细胞癌（TCC）。是一种对化疗敏感的肿瘤大多数死于泌尿系TCC。道，是由转移引起的，这是耐常规化疗。泌尿道TCC的常见转移部位是局部淋巴结、肝、肺和骨。在这些远处转移瘤中，骨转移瘤对以顺铂为基础的常规化疗始终耐药。因此，在本研究中，我们研究了新开发的米诺膦酸盐YM 529是否可以预防人TCC的溶骨性骨转移，并增强多西他赛在无胸腺裸鼠骨肿瘤模型中的作用。实验设计：在本研究中，我们通过细胞计数评估了米诺膦酸盐和/或多西他赛体外治疗对增殖的影响，通过末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）测定法诱导细胞凋亡，以及通过人、膀胱癌细胞系UMUC-14和小鼠破骨细胞中的小坑形成测定法测定成骨细胞的生物活性。在体内，我们研究了米诺膦酸盐在无胸腺裸鼠骨肿瘤模型中的作用，其中在胫骨中经皮骨内注射UMUC-14导致溶骨性骨肿瘤，作为骨转移模型。为了检测米诺膦酸盐是否可以抑制肿瘤发生并增强化疗药物多西他赛的效果，我们在骨内肿瘤植入后3天给裸鼠腹腔注射米诺膦酸盐和/或多西他赛。此外，增殖和诱导的癌细胞和破骨细胞的凋亡，在骨肿瘤的免疫组化和TUNEL检测。结果：在体外：在体外治疗多西紫杉醇抑制增殖和再吸收坑形成活性，诱导小鼠破骨细胞和UMUC-14细胞凋亡。米诺膦酸盐体外处理可抑制小鼠破骨细胞的增殖和活性并诱导细胞凋亡，但对UMUC-14细胞无影响。米诺膦酸盐治疗增强了多西他赛对破骨细胞增殖和活性的抑制作用。体内：与对照组相比，多西他赛和米诺膦酸盐联合治疗可显著降低裸鼠骨内TCC的发生率（P < 0.05），与对照组（P < 0.001）、多西他赛单药治疗（P <0.01）和米诺膦酸盐单药治疗（P < 0.05）相比，多西他赛和米诺膦酸盐联合治疗可显著降低裸鼠骨内TCC的生长。任何给药组中药物诱导的体重减轻均无显著差异。与对照组（P <0.01）、单纯氯塞韦治疗组（P <0.01）和米诺膦酸盐治疗组（P < 0.05）相比，米诺膦酸盐治疗组显著增强氯塞韦对骨肿瘤破骨细胞增殖的抑制作用。结论：米诺膦酸盐和多西他赛联合治疗对人膀胱移行细胞癌尿路骨转移患者可能有益。
Purpose: Transitional cell carcinoma (TCC). of the urinary tract is a chemosensitive tumor. Most deaths from TCC of the urinary. tract, are caused by metastasis, which is resistant to conventional chemotherapy. Frequent sites of metastases from TCC of the urinary tract are regional lymph nodes, liver, lung, and bone. Of these distant metastases, bone metastasis is consistently resistant to cisplatin-based conventional chemotherapy. Therefore, in this study, we investigated whether or not a newly developed minodronate, YM529, could prevent osteolytic bone metastasis of human TCC and also enhance the effect of docetaxel in a bone tumor model of athymic nude mice.Experimental Design: In the present study, we evaluated the effect of in vitro treatment with minodronate and/or docetaxel on the proliferation by cell count, the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and the biological activity of osteodast by pit formation assay in human, bladder cancer cell line, UMUC-14, and mouse osteoclast cells. In vivo, we examined the effect of minodronate in a bone tumor model of athymic nude mice, in which the percutaneous intraosseal injection in the tibia of UMUC-14, leads to osteolytic bone tumor, as a bone metastasis model. To examine whether or not minodronate could inhibit tumorigenicity and enhance the effect of the chemotherapeutic agent, docetaxel, we gave minodronate i.p. and/or docetaxel i.p. to nude mice 3 days after an intraosseal tumor implantation. Moreover, proliferation and the induction of apoptosis of cancer cells and osteoclasts; in bone tumors were determined by immunohistochemistry and the TUNEL assay.Results: In vitro: In vitro treatment with docetaxel inhibited proliferation and resorption pit-forming activity and induced apoptosis of mouse osteoclast cells and UMUC-14 cells. In vitro treatment with minodronate inhibited proliferation and activity and induced apoptosis of mouse osteoclast cells but not UMUC-14 cells. The treatment with minodronate enhanced the inhibition of proliferation and activity by docetaxel in osteoclasts. In vivo: In vivo combination therapy with docetaxel and minodronate significantly reduced the tumor incidence compared with the control (P < 0.05) and also growth of intraossal TCC in athymic nude mice compared with the control (P < 0.001), single therapy with docetaxel (P < 0.01), and minodronate (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment group. Therapy -with minodronate significantly enhanced inhibition of proliferation by clocetaxel in osteoclasts of bone tumors compared with the control (P < 0.01), single therapy with clocetaxel (P < 0.01), and minodronate (P < 0.05).Conclusions: These studies indicate that combination therapy with minodronate and docetaxel may be beneficial in patients with bone metastasis of human TCC in the urinary tract.