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.

口腔颌面部肿瘤的特点是口腔原发肿瘤常与骨性结构相邻。骨破坏通常会扩大手术切除的范围，并发展骨切除的需要，导致美容和功能障碍。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-470，6-O-(N-氯乙酰-氨基甲酰基)-伏马西林，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损害仍不清楚。在本研究中，我们研究了血管生成抑制剂tnp-470对口腔癌裸鼠模型骨代谢的作用机制和临床途径。1.tnp-470对骨代谢的作用机制：在1，25-二氢…的小鼠骨髓培养中。氧化维生素D3在其中更成熟。体外形成功能性破骨细胞，TNP-470可显著抑制抗酒石酸酸性磷酸酶(TRAP)阳性的多核破骨细胞样细胞的形成。TNP-470还呈剂量依赖性地抑制Vit刺激的颅骨器官培养中钙的释放。D3.2.TNP-470对动物模型溶骨性损伤的影响1)裸鼠颅骨注射IL-1β可引起严重的骨吸收，并刺激骨膜细胞的局部增殖(与未暴露于IL-1β的颅骨相比)。经IL-1β处理的小鼠的骨吸收表面存在破骨细胞。相反，TNP-470显著抑制IL-1刺激的骨吸收。2)TNP-470剂量依赖地抑制IL-1和Vit刺激的颅骨器官培养的甲状旁腺素诱导的高钙血症小鼠的血钙。通过心内注射模型，TNP-470可抑制颌骨肿瘤侵袭和溶骨性骨转移，提示TNP-470不仅通过抑制血管生成发挥抗肿瘤作用，还通过抑制破骨细胞性骨吸收来抑制骨转移。我们的结果表明，TNP-470应该是一种潜在的有益药物，用于治疗溶骨性转移。较少

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