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

恶性肿瘤体液性高钙血症（HHM）导致癌症患者生活质量下降。我们之前证明血管生成抑制剂TNP-470不仅抑制肿瘤生长，而且抑制破骨细胞骨吸收。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HHM骨代谢的影响机制和临床方法。tnf -470对体内高钙血症的影响我们采用分泌PTHrP的人口腔鳞状细胞癌OCC-1建立高钙血症模型。在治疗治疗中，在确定高钙血症后皮下给予TNP-470。在预防治疗中，在出现高钙血症前给予TNP-470。在两种治疗中，TNP-470均显著抑制血Ca^<2+>的升高。特别是在预防性治疗中，tnf -470显著抑制肿瘤生长进程，延长肿瘤生存期。在另一个由PTHrP和IL-1β诱导的实验性高钙血症模型中，TNP-470也能抑制高钙血症。血管生成抑制剂对VitD_3小鼠骨髓培养中破骨细胞形成的影响，tnf -470和血管抑制素、熊果酸均抑制破骨细胞形成。然而，其他血管生成抑制剂不能抑制破骨细胞的形成。tnp -470抑制破骨细胞形成的作用机制tnp -470抑制破骨细胞形成，但不影响破骨细胞的骨吸收活性。tnf -470不影响骨髓/基质细胞中RANKL、OPG和M-CSF mRNA的表达。TNP-470的细胞增殖抑制作用和细胞毒性在不同类型的细胞中，高浓度的TNP-470抑制细胞增殖并表现出细胞毒性。从这些结果来看，由于细胞毒性，TNP-470没有抑制破骨细胞的形成。这些数据表明，具有抗肿瘤作用和破骨细胞抑制活性的TNP-470不仅对HHM，而且对其他癌症引起的骨病都是有益的。少

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