Grant-in-Aid for international Scientific Research
|Allocation Type||Single-year Grants|
|Research Institution||KYUSHU UNIVERSITY|
KUWANO Michihiko Kyushu University, MD.Ph.D., 医学部, 教授 (80037431)
KOHNO Kimitoshi Kyushu University, MD.Ph.D., 医学部, 助教授 (00153479)
SATO Yasufummi Tohoku University, MD.Ph.D., 教授 (50178779)
ONO Mayumi Kyushu University, Ph.D., 医学部, 講師 (80128347)
KUNG Hsiang-fu National Institute of Heaith, National Cancer Institute.Ph.D., 主任
RIFKIN Daniel b New York University, Ph.D., 医学部, 教授
宮園 浩平 ルードウィヒ癌研究所, 研究主任
|Project Period (FY)
1994 – 1995
Completed(Fiscal Year 1995)
|Budget Amount *help
¥8,200,000 (Direct Cost : ¥8,200,000)
Fiscal Year 1995 : ¥3,800,000 (Direct Cost : ¥3,800,000)
Fiscal Year 1994 : ¥4,400,000 (Direct Cost : ¥4,400,000)
|Keywords||Angiogenesis / Vascular endothelial cells / Plasminogen Activator / EGF / TGFalpha / HB-EGF / TGFbeta / VEGF-VPF / IL-8 / TNFalpha / IL-8 / bFGF / 管腔形成 / 血管新生因子|
M.Kuwano, M.Ono, Y.Sato and K.Kohno have done the joint study on angiogenesis and growth factor responses in collaboration with K.Miyazono, D.Rifkin and H-f.Kung, and we obtained results as described below.
1. We have recently established angiogenesis model in vitro in wihch vascular endothelial cells on type I collagen gel in an inner chamber are co-cultured with other types of cells in an outer chamber. EGF/TGFalpha dependent tube formation of vascular endothelial cells was inhibited when human chondrocytes were co-cultured in the outer chamger. This chondrocype-induced inhibition of tube fomation was partly abrogated by administraion of anti-TGF beta antibody, suggesting that TGF beta is partly involved in the human chondrocyte-dependent avascularily.
2. Introduction of H-ras oncogene decreased the EGF binding activity to all surface EGF receptor in mouse Balb/3T3 cells. EGF receptor gene expression was abrogated in the H-ras transfectants, but co-introduction of V-myc restored the EG
F receptor to normal levels.Introduction of dominant-negative c-jun mutant encoding a transcriptionally inactive product inhibited the H-ras dependent AP-1 (Jun/Fos) induction, and also restored down-regulation of EGF binding by H-ras oncogene.
3. Oxygen radicals are induced under various pathological conditions including inflamation. Treatment with hydrogen peroxide (H_2O_2) of human microvascular endothelial cells induced development of tube-like structres, and co-administration of antisense sequence of NFkB inhibited the H_2O_2 dependent tubular morphogenesis was almost completely abrogated when anti-IL8 antibody was present. Tubular morphogenesis of vascular endothelial cells after the oxidative stimuli appeared to be associated with NFkB and IL8.
4. Irogladine used clinically as an anti-gasTriculcer agent at 10 ^<-6> to 10^<-4>M inhibited specifically cell proliferation and tube formation of vascular endothelial cells. Oral administration of irsogladine at 30 to 120 mg/kg/day inhibited both tumor growth and tumor angiogenesis when human tumor cells were transplanted in mice. Less