INVESTIGATION OF MECHANISM OF ANGIOGENESIS INHIBITOR,TNP-470 ON THE ROLE OF BONE METABOLISM AND CLINICAL APPROACH FOR HUMAN ORAL CANTER JAW INVASION IN NUDE MICE MODEL.

血管生成抑制剂 TNP-470 对骨代谢作用的机制研究以及裸鼠模型中人口腔慢下颌侵袭的临床方法。

• 批准号: 09672049
• 负责人: SASAKI Akira
• 金额: $ 1.92万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672049/
• 关键词: TNP-470; angiogenesis inhibitor; osteoclast; bone resorption; hypercalcemia; bone destruction; oral squamous cell carcinoma; jaw invasion; 悪性腫瘍

Cancer in the oral and maxillofacial region is characterized that primary tumors of the oral cavity are frequently adjacent to bony structures. Bone destruction usually extends the area of surgical excision and develops the need for bone resection, leading to cosmetic and functional disturbance. The prevention of the osteolytic bone resorption may reduce these clinically important issues. Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits osteolytic lesions induced by cancer or not. In the present study, we investigated the mechanism of angiogenesis inhibitor, tnp-470 on the role of bone metabolism and clinical approach for human oral cancer jaw invasion in nude mice model.1.Mechanism of TNP-470 on bone metabolism : In a murine bone marrow culture under 1, 25-dihyd … More roxyvitamin D3 in which mature. functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated osteoclast like cells. And also, TNP-470 dose-dependently inhibited the release of Ca from calvaria organ culture stimulated by Vit. D3. However it did not have a cytotoxic activity on the release of LDH and CPK from cultured bone marrow culture system.2.Effects of TNP-470 for the osteolytic lesions in animal models1)Daily injections of IL-1beta over the calvariae of nude mice induced a severe bone resorption and stimulated the local proliferation of the periosteal cells as compared to the calvaria not exposed to IL-1beta). Osteoclasts were present along the resorption surface of bone from a mouse treated with IL-1beta. In contrast, treatment with TNP-470 significantly inhibited the bone resorption stimulated with IL-1beta2)TNP-470 dose-dependently inhibited the serum-Ca on hypercalcemia in mouse model induce by the injection of IL-1 and PTHrP.from calvaria organ culture stimulated by Vit. D3.3)TNP-470 inhibited the progression of tumor invasion in jaw and the osteolytic bone metastasis in intracardiac injection model.These data suggested that TNP-470 inhibited bone metastasis through not only anti-tumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.(376). Less

口腔颌面部肿瘤的特点是口腔原发肿瘤常与骨结构相邻。骨破坏通常会扩大手术切除的范围，并发展为骨切除的需要，导致美观和功能障碍。预防溶骨性骨吸收可以减少这些重要的临床问题。血管生成抑制剂TNP-470, 6-O-（n -氯乙酰-氨甲酰）-富马吉尔尔是富马吉尔林的半合成类似物，对多种肿瘤的体内生长和转移具有很强的抑制活性。然而，该药是否能抑制癌症引起的溶骨性病变尚不清楚。在本研究中，我们通过裸鼠模型研究了血管生成抑制剂tnp-470对人口腔癌颌骨侵袭骨代谢的作用机制和临床途径。TNP-470对骨代谢的影响机制：在1,25 -二羟基的小鼠骨髓培养中，更多的维生素D3成熟。在体外形成的功能性破骨细胞中，TNP-470显著抑制酒石酸抗性酸性磷酸酶（TRAP）阳性的多核破骨细胞样细胞的形成。此外，tnf -470还能剂量依赖性地抑制Vit刺激的钙在颅器官培养中的释放。D3。但对骨髓培养系统中LDH和CPK的释放没有细胞毒作用。TNP-470对动物模型溶骨性病变的影响(1)与未暴露于il -1 - β的骨相比，每天在裸鼠颅骨上注射il -1 - β可诱导严重的骨吸收，并刺激局部骨膜细胞的增殖。破骨细胞沿il -1 β处理的小鼠骨的吸收表面存在。相反，tnf -470显著抑制IL-1诱导的骨吸收；tnf -470剂量依赖性地抑制Vit刺激颅器官培养的IL-1和pthrp诱导的高钙血症小鼠模型的血清钙。（3.3）心内注射模型中，TNP-470可抑制颌骨肿瘤侵袭及骨溶解性转移的进展。这些数据表明，TNP-470不仅通过抑制血管生成的抗肿瘤作用，还通过抑制破骨细胞骨吸收来抑制骨转移。我们的研究结果表明，TNP-470应该是一种潜在的有益药物，可用于治疗溶骨转移。少

项目成果

Akira Sasaki, et al.: "Angiogenesis Inhibitor TNP-470 Inhibits Human Breast Cancer Osteolytic Bone Metastasis in Nude Mice through the Reduction of Bone Resorption." Cancer Research. 58. 462-467 (1998)

Akira Sasaki 等人：“血管生成抑制剂 TNP-470 通过减少骨吸收来抑制裸鼠中人乳腺癌溶骨性骨转移。”