EXPERIMENTAL STUDY OF MECHANISM OF ANGIOGENESIS INHIBITOR, TNP-470 ON THE BONE METABOLISM AND CLINICAL APPROACH FOR HUMORAL HYPERCALCEMIA OF MARIGNANCY.

血管生成抑制剂TNP-470对骨代谢作用机制的实验研究及恶性肿瘤体液性高钙血症的临床治疗方法。

• 批准号: 12557175
• 负责人: SASAKI Akira
• 金额: $ 3.46万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557175/
• 关键词: osteoclast; oral squamous cell carsinoma; hypercalcemia; bone resorption; angiogenesis inhibitor; TNP-470; bone disease; PTHrP; 口腟扁平上皮癌; 血管新生障害剤

Humoral hypercalcemia of malignancy (HHM) causes a decline in the quality of life of cancer patients. We previously demonstrated that the angiogenesis inhibitor, TNP-470, inhibited not only tumor growth but also oeteoclastic bone resorption. It is suggested that TNP-470 has a possibility of therapeutic use for the treatment of the HHM. In the present study, we investigated the mechanism of TNP-470 on the bone metabolism and clinical approach for HHM.Effects of TNP-470 for hypercalcemia in vivoWe employed a hypercalcemia model using a human oral squamous cell carcinoma OCC-1 secreting PTHrP. In the therapeutic treatment, TNP-470 was administerd subcutaneously after the definition of hypercalcemia. In the prophylactic treatment, TNP-470 was given before manifestation of hypercalcemia. In both treatments, TNP-470 markedly suppressed the increase of blood Ca^<2+>. Particularly in the prophylactic treatment, TNP-470 significantly inhibited the progression of the tumor growth and prolonged t … More he survival.In another experimental hypercalcemia model induced by PTHrP and IL-1β, TNP-470 also suppressed hypercalcemia.Effects of angiogenesis inhibitors on osteoclasts formation in vitroIn a murine bone marrow culture under VitD_3, not only TNP-470 but also Angiostatin, Ursolic acid suppressed osteoclasts formation. However, other angiogenesis inhibitors, didn't suppress osteoclasts formation.Mechanism of the inhibitory effects on the osteoclasts formation of TNP-470TNP-470 suppressed osteoclasts formation, but didn't affect bone resorption activity of osteoclasts. TNP-470 didn't affect the expression of RANKL, OPG, and M-CSF mRNA in bone marrow/ stromal cells.Inhibitory effects of cell proliferation and Cytotoxicity of TNP-470In various types of cells, TNP-470 suppressed cell proliferation and showed cytotoxicity at a high concentration. From these results, TNP-470 didn't suppress osteoclasts formation because of cytotoxicity.These data suggested that TNP-470, which possessed both antitumor action and osteoclast-inhibitory activity, should be a beneficial drug not only for HHM but also other cancer-induced bone diseases. Less

恶性肿瘤的体液性高钙血症（HHM）导致癌症患者生活质量下降。我们以前证明，血管生成抑制剂，TNP-470，不仅抑制肿瘤生长，但也骨吸收。提示TNP-470有可能用于治疗HHM。在本研究中，我们探讨了TNP-470对骨代谢的作用机制和HHM的临床治疗方法。TNP-470对体内高钙血症的影响我们采用了一种高钙血症模型，该模型使用了分泌PTHrP的人口腔鳞状细胞癌OCC-1。在治疗中，在确定高钙血症后皮下注射TNP-470。在预防性治疗中，在出现高钙血症之前给予TNP-470。在两种处理中，TNP-470均显著抑制血Ca^<2+>的升高。特别是在预防性治疗中，TNP-470显著抑制了肿瘤生长的进展，并延长了肿瘤的生长时间。 ...更多信息 在PTHrP和IL-1β诱导的高钙血症模型中，TNP-470也能抑制高钙血症的发生。血管生成抑制剂对体外破骨细胞形成的影响在VitD_3诱导的小鼠骨髓培养中，TNP-470、Angiostatin、熊果酸均能抑制破骨细胞的形成。TNP-470抑制破骨细胞形成的机制TNP-470抑制破骨细胞的形成，但不影响破骨细胞的骨吸收活性。TNP-470对骨髓/基质细胞RANKL、OPG、M-CSF mRNA表达无影响。TNP-470的细胞增殖抑制作用和细胞毒性作用在不同类型的细胞中，TNP-470在高浓度时抑制细胞增殖并显示细胞毒性。结果表明，TNP-470对破骨细胞的形成无明显抑制作用，同时具有抗肿瘤和抑制破骨细胞的作用，不仅对HHM，而且对其它肿瘤性骨病也有一定的治疗作用。少