A Study of an anti-angiogenic thcropy targetting integrins expressed on angiogenesis endotherial cells

• Project/Area Number: 09671278
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: SUNAMURA Makoto (1998) Tohoku University, hospital, Research Associate, 医学部・附属病院, 助手 (10201584); 江川 新一 (1997) 東北大学, 医学部・附属病院, 助手 (00270679)
• Co-Investigator(Kenkyū-buntansha): SHIBUYA Kazuhiko Tohoku University, hospital, Research Associate, 医学部・附属病院, 助手 (70260429) ; 小針 雅男 東北大学, 医学部, 講師 (30170369) ; 砂村 眞琴 東北大学, 医学部・附属病院, 助手 (10201584)
• Project Period (FY): 1997 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥2,900,000 (Direct Cost: ¥2,900,000); Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: angiogenesis / microenvironment / matrix metalloproteinase / IL-12 / E-selectin / VEGF / Eセレクテン / αvβ3 / TNP-470 / 腫瘍

Research Abstract

Interleukin 12(IL-12) was proved to induce a potent antitumor and antimetastasis immune response in different models. It had also been reported that IL-12 possess anti-angiogenesis effect. The aim of this study is to clarify the anti-angiogenesis effect of IL-12 on human pancreatic carcinoma using a vital microscope system. We used severe combined immune-deficient mice (SCID). Skinfold chamber models was used to evaluate tumor growth and angiogenesis after implantation of PK-1 (pancreatic carinoma cells) or IL-12 genetically engineered PK-1 (IL-12/PK-1). Images of neovascularization were recorded though intravital microscopy and analyzed off-line. The effects of anti-IFNy and anti-IL-12 antibodies were investigated. Anti-asialo GM1 antibodi was injected to block the natural immunity. Although there was no asialo GMI antibody was injected to block the natural immunity differences in growth curve in vitro between PK-1 and IL-12/PK-.1, the growth of IL-12/PK-1 was inhibited significantly as compared with PK-1 in vivo. Skinfold chamber studies showed a strong inhibition on tumor an giogenesis of IL-12/PL-1. IL-12 antibodies administration allowed tumor development after IL-12/PK-1 implantation. It is demonstrated that anti-angiogenesis effect of IL-12 prevented the growth of panaoreatic cancer. Local delivery system of IL-12 is expected to a new strategy for pancreatic cancer.
CD62E (B-selectin, SLAM,1) expressed on endothelial cells can bind to its ligands sLeas and sLex on the surface of tumor cells. The soluble form of E-selectin was also found to promote inflammation and tumor angiogenesis. In order to study the role of CD62E in tumor microenviroment. we isolated CD62B cDNA from murine C-26 colon adcnocardnoma cell line which we found to express CD62B by FACScan. CD62E cDNA was transfected into mudne B16 melanoma cell line (B 16/B) which does not express CD62B.There was no difference between the in vibo growth of B16/E and B16 lines. The B16/E tumors grew faster than B16 tumors paralleled by rapid neovascularization when tumors were grown within the transparent chambers in SCID mice. When a new synthetic antagonist of selections, KB-R9188 was administered i-p-daily (10 mg/kg) for 20 days to SCID mico, the growth of B16/B tumores was leveled to that of B16 tumors. CD62E is revealed as an angiogenic factor.

Research Products

• [Publications] Lozonschi L., Sunamaura M.: "How can fractal analysis help underatanding tumor angiogenesis?" Microcirculation annual. 13. 19-20 (1997)