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1 (Angiogenesis Inhibitor f or Antineoplastic Therapy) 1), (chemotherapy),,., (angiogenesis), 1-2mm 3 (Folkman, 1992). (primary) (metastasis). (solid tumor)., (turn over), (cytotoxicity).,.,

2 . (endothelial cell) (phenotype).,.,,.,.. 2 ) (Endoge nous inhib itors of a ngioge nes is ) angiostatin endostatin Folkman (O'Reilly et al., 1994; 1997).. Angiostatin plasminogen metrix metalloprotease-2 (MMP-2), prostate-specific antigen (PSA), metalloelastases. Angiostatin kringle 1-4, (recombinant) angiostatin. Endostatin collagen XVIII(4), elastase. Endostatin (apoptosis) (Dhanabal et al., 1999). endostatin (regression),. Endostatin. Endostatin tropomyosin (cytoskeleton). angiostatin endostatin phase I. Angiostatin endostatin interferons (IFNs) thrombospondin. IFN hemangioma, b-fgf, (Singh et al., 1995). IFN. Thrombospondin thrombospondin, 110

Endostatin collagen XVIII(4), elastase. Endostatin (apoptosis) (Dhanabal et al., 1999). endostatin (regression),. Endostatin. Endostatin tropomyosin (cytoskeleton).

3 Bax, Bcl-2, caspase-3 (Nor et al., 2000). 3 ) (Regulation of a ngioge nic factors ) (basement membrane), (migration)..,, (invasion). (vascular endothelial growth factor, VEGF). VEGF kda, (Takahashi et al., 1995). VEGF (vascular permeablity factor), histamine 50,000 (Senger et al., 1983).. VEGF, Kaposi's sarcoma,, VEGFR-1 (flt-1), VEGFR-2 (Kdr/ flk-1), VEGFR-3 (flt-4) 3. VEGF tyrosine (dimerization). VEGFR-1, VEGFR-2. angiopoietins,. Angiopoietins (Ang) Ang-1 Ang-2, Tie-2. Ang-1, Ang-2 Tie-2 Ang-1 (vascular regression). (cooption), Ang-2 (Holash et al., 1999). (hypoxia) VEGF, Ang-1.. fibroblast growth 111

, 1983).. VEGF, Kaposi's sarcoma,, VEGFR-1 (flt-1), VEGFR-2 (Kdr/ flk-1), VEGFR-3 (flt-4) 3. VEGF tyrosine (dimerization). VEGFR-1, VEGFR-2.

4 factor (acidic and basic), transforming growth factor, epidermal growth factor (EGF), plateletderived growth factor (PDGF), platelet-derived endothelial cell growth factor, angiogenin, IL-8, MIP, PF4, GRO (Moore et al., 1998)... (ph). Src hypoxia-inducible factor (HIF)-a, promoter VEGF. Insulin like growth factor-1 -II, EGF, PDGF, hepatocyte growth factor VEGF... phosphoinositol(pi)3-kinase/ Akt HIF-a (Akagi et al., 1998), Erk-1/2 P38 MAPK (mitogen-activated protien kinase) VEGF (Jung et al., 1999; 2001a).. Von-Hippel-Lindau (VHL) p53. VHL VEGF, VHL VEGF. p53, p53 VEGF.,,. 4 ).,. VEGF,. VEGF, ribozyme,,. VEGF. Shaheen (1999) VEGF (metastasis),. 112

Insulin like growth factor-1 -II, EGF, PDGF, hepatocyte growth factor VEGF... phosphoinositol(pi)3-kinase/ Akt HIF-a (Akagi et al.

5 ,...,. (survival factor). pericytes, - integrin, VEGF, Ang-1. pericyte VEGF Ang-1 (Fujikawa et al., 1999). VEGF Akt, MAPK, IAP, A1. Ang-1 Tie-2 Akt. integrin. Integrin -. Interin a(v)b3 a(v)b5, integrin. Integrin focal adhesion kinase. VEGF Ang-1 integrin. integrin integrin.,., VEGF EGF, IGF (Perrotte et al., 1999; Jung et al., 2001b) VEGF. EGF C225. p53 VHL. angiostatin, endostatin, thrombospondin, interferon... 5 ) 113

Integrin focal adhesion kinase. VEGF Ang-1 integrin. integrin integrin.,., VEGF EGF, IGF (Perrotte et al.

6 . Fong (1999) 10, 0-85 %. Prewett (1999) Lewis VEGF, 70 %, 95 %. Lund (2000), glioblastoma TNP-470, 80 %,..,, (Jung et al., 2000)...,,,.,., spindle, pericyte. pericyte TGF-b, VEGF, Ang-1..,. Brooks (1994) integrin, Gasparini (1998). bacteriophage peptide library. Pasqualini (1997) Arg-Gly-Asp (RGD) pahge a(v) intergrin... Fidler (1999), bfgf, VEGF. IL

pericyte TGF-b, VEGF, Ang-1..,. Brooks (1994) integrin, Gasparini (1998).

7 . VEGF, bfgf, angiogenin.., pericyte coating., pericyte coating (Eberhard et al., 2000). pericytes coverage (pericyte coverage index, PCI: glioblastoma (12.7 %), renal cell carcinoma (17.9 %), (6.5 %), (67.3 %), (40.8 %), (29.6 %). Benzamin (1999) pericyte coverage VEGF,. 6 ).,,.,..,., (regression)..,.. 115

8 Table 1. Endogeno us Reg ulators of Angioge nes is Proangiogenic Growth Factors Acidic fibroblast growth factor(afgf/fgf-1) Angiogenin Basic fibroblast growth factor(bfgf/fgf-2) Fibroblast growth factor 3(FGF-3/int-2) Fibroblast growth factor 4(FGF-4/hst/K-FGF) Hepatocyte growth factor/scatter factor(hgf/sf) Interleukin-8(IL-8) Placental growth factor(pigf) Platelet derived growth factor(pdgf) Pleiotropin Proliferin Thymidine phosphorylase(tp)/platelet derived endothelial cell growth factor(pd-ecgf) Transforming growth factor(tgf)-a Transforming growth factor(tgf)-b Tumor necrosis factor(tnf)-a Vascular endothelial growth factor/vascular permeability factor(vegf/ VPF) Antiangiogenic Growth Factors Angiopoietin-2(in absence of VEGF) Angiostatin Antithrombin III fragment Endostatin Fragment of platelet factor 4(PF4) Interferon-a/b Interferon-inducible protein-10(ip-10) Maspin Meth-1 and Meth-2 Prolactin fragment Thrombospondin-1, 2 Vascular endothelial growth factor inhibitor(vegi) Vasostatin 116

3(FGF-3/int-2) Fibroblast growth factor 4(FGF-4/hst/K-FGF) Hepatocyte growth factor/scatter factor(hgf/sf) Interleukin-8(IL-8) Placental growth factor(pigf) Platelet derived growth factor(pdgf)

9 Akagi Y, Liu W, Zebrowski B et al. Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-i. Cancer Res. 1998, 58(17): Benjamin LE, Golijanin D, Itin A et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999, 103(2): Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994, 264(5158): Dhanabal M, Ramchandran R, Waterman MJ et al. Endostatin induces endothelial cell apoptosis. J Biol Chem. 1999, 274(17): Eberhard A, Kahlert S, Goede V et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 2000, 60(5): Fidler IJ, Schackert G, Zhang RD et al. The biology of melanoma brain metastasis. Cancer Metastasis Rev. 1999, 18(3): Folkman J. The role of angiogenesis in tumor growth.semin Cancer Biol. 1992, 3: Fong TA, Shawver LK, Sun L et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor(flk-1/kdr) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999, 59(1): Fujikawa K, de Aos Scherpenseel I, Jain SK et al. Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res. 1999, 253(2): Gasparini G, Brooks PC, Biganzoli E et al. Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clin Cancer Res. 1998, 4(11): Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999, 284(5422): Jung YD, Nakano K, Liu W et al. Extracellular signal-regulated kinase activation is required for up-regulation of vascular endothelial growth factor by serum starvation in human colon carcinoma cells. Cancer Res. 1999, 59(19): Jung YD, Ahmad SA, Akagi Y et al. Role of the tumor microenvironment in mediating response to anti-angiogenic therapy. Cancer Metastasis Rev. 2000, 19(1-2):

1999, 103(2): 159-65. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994, 264(5158): 569-71. Dhanabal M, Ramchandran R, Waterman MJ et al.

10 Jung YD, Liu W, Reinmuth N et al. Vascular endothelial growth factor is upregulated by interleukin-1 beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway. Angiogenesis. 2001a, 4(2): Jung YD, Kim MS, Shin BA et al. EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. Br J Cancer. 2001b, 84(6): Lund EL, Bastholm L, Kristjansen PE. Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Clin Cancer Res. 2000, 6(3): Moore BB, Arenberg DA, Addison CL et al. Tumor angiogenesis is regulated by CXC chemokines. J Lab Clin Med. 1998, 132(2): Nor JE, Mitra RS, Sutorik MM et al.thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res. 2000, 37(3): O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994, 21; 79: O'Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997, 24; 88(2): Pasqualini R, Koivunen E, Ruoslahti E. Alpha v integrins as receptors for tumor targeting by circulating ligands. Nat Biotechnol. 1997, 15(6): Perrotte P, Matsumoto T, Inoue K et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999, 5(2): Prewett M, Huber J, Li Y, Santiago A et al. Antivascular endothelial growth factor receptor(fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 1999, 59(20): Senger DR, Galli SJ, Dvorak AM et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983, 219(4587): Shaheen RM, Davis DW, Liu W et al. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis.cancer Res. 1999, 59(21): Singh RK, Gutman M, Bucana CD et al. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. PNAS. 1995, 92(10):

Br J Cancer. 2001b, 84(6): 844-50. Lund EL, Bastholm L, Kristjansen PE.

11 Takahashi Y, Kitadai Y, Bucana CD et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995, 55(18):

receptor, KDR, correlates with vascularity, metastasis,

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<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770> 2012 개원의와함께하는임상강좌 경희대학교의과대학종양혈액내과학교실 백선경 한국인사망원인 평균수명까지생존시암발생확률 길라잡이 : 개정된가이드라인을중심으로 History of anti-cancer chemotherapy Chabner BA & Roberts TG Jr. Nat Rev 2005 Use standard therapies 2012 개원의와함께하는임상강좌