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

2001 Fiscal Year Final Research Report Summary

• Project/Area Number: 12557175
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 展開研究
• Research Field: Surgical dentistry
• Research Institution: OKAYAMA UNIVERSITY
• Principal Investigator: SASAKI Akira GRADUATE SCHOOL OF MEDICINE AND DENTISTRY, OKAYAMA UNIVERSITY, ASSOCIATE PROFESSOR, 大学院・医歯学総合研究科, 助教授 (00170663)
• Co-Investigator(Kenkyū-buntansha): KUSAKA Masami TAKEDA CHEMICAL INDUSTRIES LTD, CHIEF INVESTIGATOR, 創薬研究本部創薬第二研究所, 主任研究員 ; MESE Hiroshi GRADUATE SCHOOL OF MEDICINE AND DENTISTRY, OKAYAMA UNIVERSITY, INSTRUCTOR, 大学院・医歯学総合研究科, 助手 (40325098)
• Project Period (FY): 2000 – 2001
• Keywords: osteoclast / oral squamous cell carsinoma / hypercalcemia / bone resorption / angiogenesis inhibitor / TNP-470 / bone disease / PTHrP

Research Abstract

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 vivo
We 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 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 vitro
In 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-470
TNP-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-470
In 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.