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

点击翻译按钮获取中文摘要

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