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.

口腔颌面部癌症的特征是口腔原发性肿瘤经常邻近骨性结构。骨破坏通常会扩大手术切除的范围，并需要进行骨切除，导致外观和功能障碍。预防溶骨性骨吸收可能会减少这些临床上重要的问题。血管生成抑制剂TNP-470是烟曲霉素的半合成类似物6-O-（N-氯乙酰基-氨甲酰基）-烟曲霉醇（6-O-（N-chloroacetyl-carbamoyl）-fumagilol），对多种肿瘤的生长和转移有较强的抑制作用。然而，它仍然是未知的，是否这种代理人抑制溶骨性病变所诱导的癌症或没有。本研究以裸鼠口腔癌颌骨侵袭模型为动物模型，探讨了血管生成抑制剂TNP-470对骨代谢的影响机制，并探讨了TNP-470治疗口腔癌颌骨侵袭的临床途径。 ...更多信息 维生素D3在其中成熟。在体外形成的功能性破骨细胞中，TNP-470显著抑制抗酒石酸酸性磷酸酶（TRAP）阳性多核破骨细胞样细胞的形成。TNP-470剂量依赖性地抑制Vit刺激的大鼠颅盖器官培养液中Ca的释放。D3. 2. TNP-470对溶骨性病变动物模型的影响1）每天在裸鼠颅骨上注射IL-1 β，与未注射IL-1 β的颅骨相比，可引起严重的骨吸收，并刺激局部骨膜细胞增殖。破骨细胞沿着骨吸收表面，从一个小鼠用IL-1 β治疗。2）TNP-470剂量依赖性地抑制IL-1 β诱导的小鼠高钙血症和Vit刺激的小鼠颅骨器官培养物PTHrP诱导的血清Ca。D3.3）TNP-470可抑制颌骨肿瘤的侵袭和心内注射模型中溶骨性骨转移，这些数据表明TNP-470不仅通过其抑制血管生成的抗肿瘤作用，而且通过抑制骨细胞骨吸收来抑制骨转移。我们的研究结果表明，TNP-470应该是一个潜在的有益的药物，用于治疗溶骨性转移。（376）。少

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