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Inhibition of Tumor Growth and Metastasis by Targeting Tumor-Associated Angiogenesis with Antagonists to the Receptors of Vascular Endothelial Growth Factor

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Abstract

Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical and pre-clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent good targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. We have produced a panel of antibodies directed against the VEGF receptor 2, KDR/Flk-1. These antibodies potently block VEGF/KDR/Flk-1 interaction, and inhibit VEGF-stimulated activation of the receptor and proliferation of human endothelial cells. Further, the antibodies significantly inhibited tumor-associated angiogenesis in several animal models. Antagonists of VEGF and/or its receptors may offer higher specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy. Anti-angiogenesis therapy represents a novel strategy for the treatment of cancer and other human disorders where pathological angiogenesis is involved.

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References

  1. Folkman J: Tumor angiogenesis: therapeutic implications.N Engl J Med 285: 1182–1186, 1971

    Google Scholar 

  2. Folkman J: What is the evidence that tumors are angiogenesis-dependent? J Natl Cancer Inst 82: 4–6, 1991

    Google Scholar 

  3. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease.Nat Med 1: 27–31, 1995

    Google Scholar 

  4. Zetter BR: Angiogenesis and tumor metastasis.Annu Rev Med 49: 407–424, 1998

    Google Scholar 

  5. Weinstat-Saslow D, Steeg PS: Angiogenesis and colonization in the tumor metastatic process: basic and applied advances.FASEB J 8: 401–407, 1994

    Google Scholar 

  6. Liotta LA, Steep PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of negative and positive regulation, Cell 64: 327–336, 1991

    Google Scholar 

  7. Fidler IT, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis.Cell 79: 185–188, 1994

    Google Scholar 

  8. Klagsbrun M, D'Amore PA: Regulators of angiogenesis.Annu Rev Physiol 53: 217–239, 1991

    Google Scholar 

  9. Folkman J, Klagsbrun M: Angiogenesis factors.Science 235: 442–447, 1987

    Google Scholar 

  10. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen.Science 246: 1306–1309, 1989

    Google Scholar 

  11. Ferrara N: The role of vascular endothelial growth factor in pathological angiogenesis.Breast Cancer Res & Treat 36: 127–137, 1995

    Google Scholar 

  12. Ferrara N: Vascular endothelial growth factor.Trends Cardiovasc Med 3: 244–250, 1993

    Google Scholar 

  13. Brown LF, Detmar, M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A multifunctional angiogenic cytokine.In: Goldberg ID, Rosen EM (eds), Regulation of Angiogenesis.Birkhauser Verlag, Basel/Switzerland, 1997, pp 233–269

    Google Scholar 

  14. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.Nature 380: 439–442, 1996

    Google Scholar 

  15. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens K, Gertsenstein M, Farhig M, Vandenhoeck A, Harpal K, Eberhardt C, Deciercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Nature 380: 435–439, 1996

    Google Scholar 

  16. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breltman ML, Schuh AC: Failure of blood-island formation and vasculogenesis in F1k-1-deficient mice.Nature 376: 62–66, 1995

    Google Scholar 

  17. Shalaby F, Ho J, Stanford WL, Klaus-Dieter F, Schuh AC, Schwartz L, Bernstein A, Rossant J: A requirement for F1k1 in primitive and definitive hematopoicsis and vasculogenesis.Cell 89: 981–990, 1997

    Google Scholar 

  18. Fong GH, Rossant J, Gertsenstein M, Breitman ML: Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.Nature 376: 66–70, 1995

    Google Scholar 

  19. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominantnegative F1k-1 mutant.Nature 367: 576–579, 1994

    Google Scholar 

  20. Kim J, Li B, Winer J, Armanini M, Gillett N, Phillip HS, Ferrara N: Inhibition of vascular endothelial growth factorinduced angiogenesis suppresses tumor growth in vivo.Nature 362: 841–844, 1993

    Google Scholar 

  21. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusening NE: Halting angiogenesis suppresses carcinoma cell invasion.Nat Med 3: 1222–1227, 1997

    Google Scholar 

  22. Pluda JM: Tumor-associated angiogenesis: Mechanisms, clinical implications, and therapeutic strategies.Semi Oncol 24: 203–218, 1997

    Google Scholar 

  23. Gradishar W: An overview of clinical trials involving inhibitors of angiogenesis and their mechanism of action.Invest New Drugs 15: 49–59, 1997

    Google Scholar 

  24. Wolfe MS: Angiogenesis.IDrugs 1: 22–25, 1998

    Google Scholar 

  25. Klagsbrun M, D'Amore PA: Vascular endothelial growth factor and its receptors.Cytokine Growth Factor Rev 7: 259–270, 1996

    Google Scholar 

  26. Maglione D, Guerriero V, Viglietto G, Delli Bovi P, Persico MG: Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor.Proc Natl Acad Sci USA 88: 9267–9271, 1991

    Google Scholar 

  27. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U: Vascular endothelial growth factor B, a novel growth factor for endothelial cells.Proc Natl Acad Sci USA 93: 2576–2581, 1996

    Google Scholar 

  28. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K: VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development 122: 3829–3837, 1996

    Google Scholar 

  29. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA: Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinase VEGF receptor 2 (F1k1) and VEGF receptor 3 (Flt4).Proc Natl Acad Sci USA 95: 548–553, 1998

    Google Scholar 

  30. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW: The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA.Mol Endocrinol 5: 1806–1814, 1991

    Google Scholar 

  31. Tischer E, Mitchell R, Hartmann T, Silva M, Gospodarowicz D, Fiddes J, Abraham J: The human gene for vascular endothelial growth factor.J Biol Chem 266: 11947–11954, 1991

    Google Scholar 

  32. Keyt BA, Berleau LT, Nguyen HV, Chen C, Heinsohn H, Vandlen R, Ferrera N: The carboxy-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency.J Biol Chem 271: 7788–7795, 1996

    Google Scholar 

  33. Houck KA, Leung DW, Rowland AM, Winer J, Ferrera N: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms.J Biol Chem 267: 26031–26037, 1992

    Google Scholar 

  34. Keyt BA, Nguyen HV, Berleau LT, Duarte CM, Park J, Chen C, Ferrera N: Identification of vascular endothelial growth factor determinants for binding KDR and Flt-1 receptors.J Biol Chem 271: 5638–5646, 1996

    Google Scholar 

  35. Soker S, Gollamudi-Payne S, Fidder H, Charmahelli H, Klagbrun M: Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165.J Biol Chem 272: 31582–31588, 1997

    Google Scholar 

  36. DiSalvo J, Bayne ML, Conn G, Kwok, PW, Trivedi, PG, Soderman, DD, Palisi, TM, Sullivan KA, Thomas, KA: Purification and characterization of a naturally occurring vascular endothelial growth factor/placenta growth factor heterodimer.J Biol Chem 270: 7717–7723, 1995

    Google Scholar 

  37. Cao Y, Chen H, Zhou L, Chiang MK, Anand-Apte B, Weatherbee JA, Wang Y, Fang F, Flanagan JG, Tsang MLS: Heterodimers of placenta growth factor/vascular endothelial growth factor.Endothelial activity, tumor cell expression, and high affinity binding to F1k-1/KDR.J Biol Chem 271: 3154–3162, 1996

    Google Scholar 

  38. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K: Protoeolytic processing regulates receptor specificity and activity of VEGFC.EMBO J 16: 3898–3911, 1997

    Google Scholar 

  39. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Sxxx M, Fukumura D, Jain RK, Alitalo K: Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.Science 276: 1423–1425, 1997

    Google Scholar 

  40. Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JEG, Weich HA, Christ B, Alitalo K, Wilting J: VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane.Dev Biol 188: 96–109, 1997

    Google Scholar 

  41. Joukov V, Pajusola K, Paipainen, A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.EMBO J 15: 290–298, 1996

    Google Scholar 

  42. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI: Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4.Proc Natl Acad Sci USA 93: 1988–1992, 1996

    Google Scholar 

  43. Orlandini M, Marconcini L, Ferruzzi R, Oliviero S: Identification of a c-fos-induced gene that is related to the platelet-derived.growth factor/vascular endothelial growth factor family.Proc Natl Acad Sci USA 93: 11675–11680, 1996

    Google Scholar 

  44. Pepper MS, Mandriota SJ, Jeltsch M, Kumar V, Alitalo K: Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity.J Cell Physiol 177: 439–452, 1998

    Google Scholar 

  45. Lyttle DJ, Fraser KM, Flemings SE, Mercer AA, Robinson AJ: Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus.J Virol 68: 84–92, 1994

    Google Scholar 

  46. Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M: A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/F1k-1 receptor and carries a potent mitotic activity without heparin-binding domain.J Biol Chem 273: 31273–31282, 1998

    Google Scholar 

  47. Wise LM, Veikkola T, Mercer AA, Savory LJ, Fleming SE, Caesar C, Vitali A, Makinen T, Alitalo K, Stacker SA: Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1.Proc Natl Acad Sci USA 96: 3071–3076, 1999

    Google Scholar 

  48. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M: Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt-1) closely related to the fms family.Oncogene 5: 519–524, 1990

    Google Scholar 

  49. De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.Science 255: 989–991, 1992

    Google Scholar 

  50. Terman BI, Dougher-Vermazen M, Carrion ME, Dimtrov D, Armellino DC, Gospodarowicz D, Bohlen P: Identification of the KDR tyrosine kinase receptor as a receptor for vascular endothelial growth factor.Biochem Biophys Res Commun 187: 1579–1586, 1992

    Google Scholar 

  51. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NPH, Risau W, Ullrich A: High affinity VEGF binding and developmental expression suggest F1k-1 as a major regulator of vasculogenesis and angiogenesis.Cell 72: 835–846, 1993

    Google Scholar 

  52. Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT: Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium.Proc Natl Acad Sci USA 90: 7533–7537, 1993

    Google Scholar 

  53. Peters KG, De Vries C, Williams LT: Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth.Proc Natl Acad Sci USA 90: 8915–8919, 1993

    Google Scholar 

  54. Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K: FLT-4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines.Cancer Res 52: 5738–5743, 1992

    Google Scholar 

  55. Galland F, Karamysheva A, Pebusque MJ, Borg JP, Rottapel R, Dubreuil P, Posnet O, Birnbaum D: The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor.Oncogene 8: 1233–1240, 1993

    Google Scholar 

  56. Soker S, Fidder H, Neufeld G, Klagsbrun M: Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain.J Biol Chem 271: 5761–5767, 1996

    Google Scholar 

  57. Soker S, Takashima S, Miao HQ, Neufeld, Klagsbrun M: Neuropilin-l is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell 92: 735–745, 1998

    Google Scholar 

  58. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.J Biol Chem 269: 26988–26995, 1994

    Google Scholar 

  59. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi M, Shibuya M: A unique signal transduction pathway for the FLT tyrosine kinase, a receptor for vascular endothelial growth factor.Oncogene 10: 135–137, 1995

    Google Scholar 

  60. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D: Migrrttion of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1.Blood 87: 3336–3343, 1996

    Google Scholar 

  61. Clauss M, Weich HA, Breier G, Knies U, Rockl W, Waltenberger J, Risau W: The vascular endolhelial growth factor receptor Flt-1 mediates biological activities.Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis.J Biol Chem 271: 17629–17634, 1996

    Google Scholar 

  62. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M: Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice.Proc Natl Acad Sci USA 95: 9349–9354, 1998

    Google Scholar 

  63. Kendall RL, Thomas KA: Inhibition of vascular endothelial growth factor activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci 90: 10705–10709, 1993

    Google Scholar 

  64. Goldman CK, Kendall RL, Cabrera G, Sorocaenu L, Heike Y, Gillespie GY, Siegal GP, Mao X, Bett AJ, Huckle WR, Thomao KA, Curiel DT: Paracrine expression of a native soluble vascular growth factor receptor inhibits tumor growth, metasta4is, and mortality rate.Proc Natl Acad Sci USA 95: 8795–8800, 1998

    Google Scholar 

  65. Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR: A receptor tyrosine cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit..Proc Natl Acad Sci USA 88: 9026–9030, 1991

    Google Scholar 

  66. Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM: Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site.Proc Natl Acad Sci USA 94: 7192–7197, 1997

    Google Scholar 

  67. Barleon B, Totzke F, Herzog C, Blanke S, Kremmer E, Siemeister G, Marmé D, Martiny-Baron G: Mapping of the sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor FLT-1.J Biol Chem 272: 10382–10388, 1997

    Google Scholar 

  68. Fuh G, Li B, Crowley C, Cunningham B, Wells JA: Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor, J Biol Chem 273: 11197–11204, 1998

    Google Scholar 

  69. Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM: Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.Cell 91, 695–704, 1997

    Google Scholar 

  70. Kaplan JB, Sridharan L, Zaccardi JA, Dougher-Vermazen M, Terman BI: Characterization of a soluble vascular endothelial growth factor receptor-immunoglobulin chimera.Growth Factors 14: 243–256, 1997 Shinkai A, Ito M, Anazawa H, Yamaguchi S, Shitara K, Shibuya M: Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor.J Biol Chem 273: 31282-31288, 1998

    Google Scholar 

  71. Shinkai A, Ito M, Anazawa H, Yamaguchi S, Shitara K, Shibuya M: Mapping of the site involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor.J Biol Chem 273: 31282–31288, 1998

    Google Scholar 

  72. Cunningham SA, Stephan CC, Arrate PM, Ayer KG, Brock TA: Identification of the extracellular domains of Flt-1 that mediate ligand interactions.Biochem and Biophys Res Commun 231: 596–599, 1997

    Google Scholar 

  73. Davis-Smith T, Presta LG, Ferrara N: Mapping the charged residues in the second immunoglobulin-like domain of the vascular endothelial growth factor/placenta growth factor receptor Flt-1 required for binding and structural stability.J Biol Chem 273: 3216–3222, 1998

    Google Scholar 

  74. Davis-Smyth T, Chen H, Park J, Presta LG, Ferrara N: The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade.EMBO J 15: 4919–4927, 1996

    Google Scholar 

  75. Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor.Potentiation of vascular growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to F1k-1/KDR.J Biol Chem 269: 25646–25654, 1994

    Google Scholar 

  76. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity.Cell 61: 203–212, 1990

    Google Scholar 

  77. Merenmies J, Parada LF, Henkemeyer M: Receptor tyrosine kinases signaling in vascular development.Cell Growth Diff 8: 3–10, 1997

    Google Scholar 

  78. Fanti WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT: Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways.Cell 69: 413–423, 1992

    Google Scholar 

  79. Valius M, Kazlauskas A: Phosholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal.Cell 73: 321–334, 1993

    Google Scholar 

  80. Heldin CH: Dimerization of cell surface receptors in signal transduction.Cell 80: 213–223, 1995

    Google Scholar 

  81. Dougher-Vermazen M, Hulmes JD, Bohlen P, Terman BI: Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor.Biochem Biophys Res Commun 205: 728–738, 1994

    Google Scholar 

  82. Ito N, Wernstedt C, Engström, Claesson-Welsh L: Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules.J Biol Chem 273: 23410–23418, 1998

    Google Scholar 

  83. Guo D, Jia Q, Song HY, Warren RS, Donner DB: Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains Association with endothelial cell proliferation.J Biol Chem 270: 6729–6733, 1995

    Google Scholar 

  84. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 30-kinase/akt signal transduction pathway.J Biol Chem 273: 30336–30343, 1998

    Google Scholar 

  85. Abedi H, Zachary I: Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelialcells.J Biol Chem 274: 15442–15451, 1997

    Google Scholar 

  86. Kroll J, Waltenberger J: The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells.J Biol Chem 272: 32521–32527, 1997

    Google Scholar 

  87. Fournier E, Rosnet O, Marchetto S, Turck CW, Rottapel R, Pelicci PG, Birnbaum D, Borg JP: Interaction with the phosphotyrosine binding domain/phosphotyrosine interacting domain of SHC is required for the transforming activity of the FLT4/VEGFR3 receptor tyrosine kinase.J Biol Chem 271: 12956–12963, 1996

    Google Scholar 

  88. Takahashi T, Shibuya M: The 230 kDa mature form of KDR/F1k-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts.Oncogene 20: 2079–2089, 1997

    Google Scholar 

  89. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract.Cancer Res 53: 4727–4735, 1993

    Google Scholar 

  90. Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer.Human Path 26: 86–91, 1995

    Google Scholar 

  91. Guidi A, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF, Brown LF: Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia.J Natl Cancer Inst 87: 1237–1245, 1995

    Google Scholar 

  92. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR: Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas.Am J Pathol 143: 1255–1262, 1993

    Google Scholar 

  93. Olson TA, Mohanraj D, Carson LF, Ramakrishnan S: Vascular permeability factor gene expression in normal and neoplastic human ovaries.Cancer Res 54: 276–280, 1994

    Google Scholar 

  94. Guidi AJ, Abu-Jawdeh G, Tognazzi K, Dvorak HF, Brown LF: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma.Cancer 78: 454–460, 1996

    Google Scholar 

  95. Brown LF, Tognazzi K, Dvorak H, Harrist T: Strong expression of KDR, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi's sarcoma and cutaneous angiosarcoma.Am J Pathol148: 1065–1074, 1995

    Google Scholar 

  96. Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumor angiogenesis factor in human glioma in vivo.Nature 359: 845–848, 1992

    Google Scholar 

  97. Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH: Expression of vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms.J Clin Invest 91: 153–159, 1993

    Google Scholar 

  98. Wizigmann-Voos S, Breier G, Risau W, Plate KH: Upregulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas.Cancer Res 55: 1358–1364, 1995

    Google Scholar 

  99. Bellamy WT, Richter L, Frutiger Y, Grogan TM: Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies.Cancer Res 59: 28–733, 1999

    Google Scholar 

  100. Weidner N, Semple P, Welch W, Folkman J: Tumor angiogenesis and metastasis.Correlation in invasive breast carcinoma.N Engl J Med 324: 1–6, 1991

    Google Scholar 

  101. Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG, Nichols PW: Angiogenesis in bladder cancer: Relationship between microvessel density and tumor prognosis.J Natl Cancer Inst 87: 1603–1612, 1995

    Google Scholar 

  102. Bigler SA, Deering RE, Brawer MK: Comparison of microscopic vascularity in benign and malignant prostatic tissue.Human Pathol 24: 220–226, 1993

    Google Scholar 

  103. Gasparini G, Bonoldi E, Viale G, Verderio P, Boracchi P, Panizzoni GA, Radaelli U, Di Bacco A, Guglielmi RE, Bevilacqua P: Prognostic and predictive value of tumor angiogenesis in ovarian carcinomas.Int J Cancer 69: 205–211, 1996

    Google Scholar 

  104. Lindmark G, Gerdin B, Sundberg C Pahlman L, Bergstrom R, Glimelius B: Prognostic significance of the microvascular count in colorectal cancer.J Clin Oncol 14: 461–466, 1996

    Google Scholar 

  105. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T, Horiuchi T, Muraoka R, Iki M: Extent of tumor vascularization correlates with prognosis and hematogenous metastasis in gastric carcinoma.Cancer Res 56: 2671–2676, 1996

    Google Scholar 

  106. Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA: Relation of neovascularisation to metastasis of non-small cell lung cancer.Lancet 340: 145–146, 1992

    Google Scholar 

  107. Sillman F, Boyce J, Fruchter R: The significance of atypical vessels and neovascularization in cervical neoplasias.Am J Obstet Gynecol 139: 154–157, 1981

    Google Scholar 

  108. Barnhill RL, Fandrey K, Levy MA, Mihm MC Jr., Hyman B: Angiogenesis and tumor progression of melanoma.Quantification of vascularity in melanocytic nevi and cutaneous malignant melanoma.Lab Invest 67: 331–337, 1992

    Google Scholar 

  109. Olivarez D, Ulbright T, DeRiese W, Foster R, Reister T, Einhorn L, Sledge G: Neovascularization in clinical stage A testicular germ cell tumor: prediction of metastatic disease.Cancer Res 54: 2800–2802, 1994

    Google Scholar 

  110. Gasparini G, Weidner N, Maluta S Pozza F, Boracchi P, Mezzetti M, Testolin A, Bevilacqua P: Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and neck squamous-cell carcinomas.Int J Cancer 57: 739–744, 1993

    Google Scholar 

  111. Li VW, Folkerth RD, Watanabe H, Yu C, Rupnick M, Barnes P, Scott RM, Black PM, Sallan SE, Folkman J: Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumors.Lancet 344: 82–86, 1994

    Google Scholar 

  112. Plate KH, Breier G, Millauer B, Ullrich A, Risau W: Upregulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis.Cancer Res 53: 5822–5827, 1993

    Google Scholar 

  113. Zhang HT, Craft P, Scott PA, Ziche M, Weich HA, Harris AL, Bicknell R: Enhancement of tumor growth and vascular density by transfection of vascular endothelial growth factor into MCF-7 human breast carcinoma cells.J Natl Cancer Inst 87: 213–219, 1995

    Google Scholar 

  114. Ferrara N, Winer J, Burton T, Rowland A, Siegel M, Phillips HS, Terrell T, Keller GA, Levinson AD: Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells.J Clin Invest 91: 160–170, 1993

    Google Scholar 

  115. Rockwell P, Neufeld G, Glassman A, Caron D, and Goldstein N: in vitro neutralization of vascular endothelial growth factor activation of F1k-1 by a monoclonal antibody.Mol Cell Differ 3: 91–109, 1995

    Google Scholar 

  116. Zhu Z, Rockwell P, Lu D, Kotanides H, Pytowski B, Hicklin DJ, Bohlen P, Witte L: Inhibition of vascular endothelial growth factor induced receptor activation with antikinase insert domain-containing receptor single-chain antibodies from a phage display library.Cancer Res 58: 3209–3214, 1998

    Google Scholar 

  117. Zhu Z, Lu D, Kotanides H, Santiago A, Jimenea X, Simcox T, Hicklin DJ, Bohlen P, Witte L: Inhibition of vascular endothelial growth factor induced mitogenesis of human endothelial cells by a chimeric anti-KDR receptor antibody.Cancer Lett 1999, in press

  118. Saleh M, Stacker SA, Wilks AF: Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence.Cancer Res 56: 393–401, 1996.

    Google Scholar 

  119. Ramakrishnan S, Olson TA, Bautch VL, Mohanraj D: Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/Flk-l-positive endothelial cell proliferation in vitro and angiogenesis in vivo.Cancer Res 56: 1324–1330, 1996

    Google Scholar 

  120. Arora N, Masood R, Zheng T, Cai J, Smith DL, Gill PS: Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells.Cancer Res 59: 183–188, 1999

    Google Scholar 

  121. Lin P, Sankar S, Shan S, Dewhirst MW, Polverini PJ, Quinn TQ, Peters KG: Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor.Cell Growth Diff 9: 49–58, 1998

    Google Scholar 

  122. Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang, C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK: F1k-1 as a target for tumor growth inhibition.Cancer Res 56: 3540–3545, 1996

    Google Scholar 

  123. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell JT, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth PK, McMahon G: SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (F1k-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.Cancer Res 59: 99–106, 1999

    Google Scholar 

  124. Boehm T, Folkman J, Browder T, O'Reilly MS: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.Nature 390: 404–407, 1997

    Google Scholar 

  125. Kerbel RS: A cancer therapy resistant to resistance (News and Views).Nature 390: 335–336, 1997

    Google Scholar 

  126. Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, Bohlen P: Monoclonal antibodies targeting the VEGF receptor-2 (F1k-1/KDR) as an anti-angiogenic therapeutic strategy, Cancer Met Rev 17: 155–161, 1998

    Google Scholar 

  127. Brekken RA, Huang X, King SW, Thorpe PE: Vascular endothelial growth factor as a marker of tumor endothelium.Cancer Res 58: 1952–1959, 1998

    Google Scholar 

  128. Presta L, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N: Humanization of an antivascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.Cancer Res 57: 4593–4599, 1997

    Google Scholar 

  129. Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis.Science 264: 569–571, 1994

    Google Scholar 

  130. Rockwell P, Goldstein N: Role of protein tyrosine kinase receptors in cancer: possibilities for therapeutic intervention.Mole Cell Diff 3: 315–335, 1995

    Google Scholar 

  131. Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA: Antiintegrin blocks human breast cancer growth and angiogenesis in human skin.J Clin Invest 96: 1815–1822, 1995

    Google Scholar 

  132. Juhasz I, Albelda SM, Elder DE, Murphys GF, Adachi K, Herlyn D, Valyi-Nagy IT, Herlyn M: Growth and invasion of human melanomas in human skin grafted to immunodeficient mice.Am J Path 143: 528–531, 1993

    Google Scholar 

  133. Kusaka S, Hicklin DJ, Witte I, Bohlen P, Burlingham WJ: Effect of anti-VEGF receptor monoclonal antibodies on tumor growth and angiogenesis in SCID mouse/human skin graft model (Abstract).Amer Asso for Cancer Res 40: 68, 1999

    Google Scholar 

  134. Hawkins MJ: Clinical trials of antiangiogenic agents.Curr Opin Oncol 7: 90–93, 1995

    Google Scholar 

  135. Ogilvie DJ: ZD4190: an inhibitor of signal tranduction with anti-tumor activity.In: Angiogenesis: Novel Therapeutic Development.IBC Fifth Annual International Conference.Boston, MA, 1999

  136. Sandberg JA: Pharmacology and toxicity of an antiangiogenic ribozyme.In: Angiogenesis: Novel Therapeutic Development.IBC Fifth Annual International Conference.Boston, MA, 1999

  137. Neri D, Carnemolla B, Nissim A, Leprini A, Querzè G, Balza E, Pini A, Tarli L, Halin C, Neri P, Zardi L, Winter G: Targeting by affinity-matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform.Nat Biotechnol 15: 1271–1275, 1997

    Google Scholar 

  138. Viti F, Tarli L, Giovannoni L, Zardi L, Neri D: Increased binding affinity and valence of recombinant antibody fragments lead to improved targeting of tumoral angiogenesis.Cancer Res 59: 347–353, 1999

    Google Scholar 

  139. Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE: Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature.Science 275: 547–550, 1997

    Google Scholar 

  140. Matsuno F, Haruta Y, Kondo M, Tsai H, Barcos M, Seon BK: Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vascular using two new anti-endoglin monoclonal antibodies.Clin Cancer Res 5: 371–382, 1999

    Google Scholar 

  141. Spragg DD, Alford DR, Greferath R, Larsen CE, Lee KD, Gurtner GC, Cybulsky MI, Tosi PF, Nicolau C, Gimbrone MA: Immunotargeting ofliposomes to activated vascular endothelial cells: A strategy for site-selective delivery in the cardiovascular system.Proc Natl Acad Sci USA 94: 8795–8800, 1997

    Google Scholar 

  142. Arap W, Pasqualini R, Ruoslahti E: Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model.Science 279: 377–380, 1998

    Google Scholar 

  143. Piccoli R, Olson KA, Vallee BL, Fett JW: Chimeric antiangiogenin antibody cAb 26-2F inhibits the formation of human breast cancer xenografts in athymic mice.Proc Natl Acad Sci USA 95: 4579–4583, 1998

    Google Scholar 

  144. Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE, Peters KG: Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2.Proc Natl Acad Sci USA 95: 8829–8834, 1998

    Google Scholar 

  145. Siemeister G, Schirner M, Reusch P, Barleon B, Marmé D, Martiny-Baron G: An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells.Proc Natl Acad Sci USA 95: 4625–4629, 1998

    Google Scholar 

  146. Powell WC, Matrisian LM: Complex roles of matrix metalloproteinases in tumor progression.Curr Top Microbiol Immunol 213: 1–21, 1996

    Google Scholar 

  147. Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth.Nature 348: 555–557, 1990.

    Google Scholar 

  148. Kusaka M, Sudo K, Fujita T: Potent anti-angiogenic action of AGM-1470: Comparison to the fumagillin parent.Biochem Biophys Res Commun 174: 1070–1076, 1991

    Google Scholar 

  149. Berm H, Folkman J: Analysis of experimental antiangiogenic therapy.J Fed Surg 28: 445–451, 1993

    Google Scholar 

  150. Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM: The antiangiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2.Proc Natl Acad Sci USA 94: 6099–6103, 1997

    Google Scholar 

  151. D'Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis.Proc Natl Acad Sci USA 91: 4082–4085, 1994

    Google Scholar 

  152. Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Amato RJ, Folkman J: Inhibition of angiogenesis in vivo by interleukin12.J Natl Cancer Inst 87: 581–586, 1995

    Google Scholar 

  153. Strieter RM, Kunkel SL, Arenberg DA, Burdick MD, Polverini PJ: Interferon gamma-inducible protien 10 (IP-IO), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis.Biochem Biophys Res Commun 201: 51–57, 1995

    Google Scholar 

  154. Sgadari C, Angiolillo AL, Tosato G: Inhibition of angiogenesis by interleukin 12 is mediated by the interferon-inducible protein 10.Blood 87: 3877–3882, 1996

    Google Scholar 

  155. Hellerqvist CG, Thurman GB, Page DL, Wang YF, Russel BA, Montgomery CA, Sundell HW: Anti-tumor effects of GBS toxin: a polysaccharide exotoxin from group B b-hemolytic streptococcus.J Cancer Res Clin Oncol 120: 63–70, 1993

    Google Scholar 

  156. Yan H, Carter CE, Wang E, Page DL, Washington K, Wamil ED, Yakes FM, Thurman GB, Hellerqvist CG: Functional studies on the anti-pathoangiogenic properties of CMIOI.Angiogenesis 2: 219–233, 1999

    Google Scholar 

  157. Thurman GB, Russel BA, York GE, Wang YF, Page DL, Sundell HW, Hellerqvist CG: Effects of GBS toxin on long term survival of mice bearing transplanted Madison lung tumors.J Cancer Res Clin Oncol 120: 479–484, 1994

    Google Scholar 

  158. DeVore RF, Hellerqvist CG, Wakefield, ED, Wamil ED, Thurman GB, Minton PA, Sundell HW, Yan HP, Carter CE, Wang YF, York GE, Zhang MH, Johnson DH: A phase I study of the anti-neovascularization drug CM101.J Clin Cancer Res 3: 365–372, 1997

    Google Scholar 

  159. Kohn EC, Reed E, Sarosy G, Christian M, Link CJ, Cole K, Figg WD, Davis PA, Jacob J, Goldspiel B, Liotta LA: Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.Cancer Res 56: 569–573, 1996

    Google Scholar 

  160. Sills AK Jr, Williams JI, Tyler BM, Epstein DS, Sipos EP, Davis JD, McLane MP, Pitchford S, Cheshire K, Gannon FH, Kinney WA, Chao TL, Donowitz M, Laterra J, Zasloff M, Brem H: Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.Cancer Res 58: 2784–1792, 1998

    Google Scholar 

  161. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis lung carcinoma.Cell 79: 315–328, 1994

    Google Scholar 

  162. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.Cell 88: 277–285, 1997

    Google Scholar 

  163. O'Reilly MS, Holmgren L, Chen C, Folkman J: Angiostatin induces and sustains dormancy of human primary tumors in mice.Nat Med 2: 689–692, 1996

    Google Scholar 

  164. Dhanabal M, Ramchandran R, Volk R, Stillman IE, Lombardo M, Iruela-Arispe ML, Simons M, Sukhatme VP: Endostatin: Yeast production, mutants, and antitumor effects in renal cell carcinoma.Cancer Res 59: 189–197, 1999

    Google Scholar 

  165. Wu Z, O'Reilly MS, Folkman J, Shing Y: Suppression of tumor growth with recombinant murine angiostatin.Biochem Biophys Res Commun 236: 651–654, 1997

    Google Scholar 

  166. Tanaka T, Cao Y, Folkman J, Fine HA: Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA.Cancer Res 58: 3362–3369, 1998

    Google Scholar 

  167. Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C, Perricaudet M, Yeh P, Lu H: Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest.Proc Natl Acad Sci USA 95: 6367–6372, 1998

    Google Scholar 

  168. Lucas R, Holmgren L, Jimenez B, Mandrota SJ, Borlat F, Sim BK, Wu Z, Grau GE, Shing Y, Soff GA, Bouck N, Pepper MS: Multiple forms of angiostatin induce apoptosis in endothelial cells.Blood 92: 4730–4741, 1998

    Google Scholar 

  169. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O'Reilly M, Folkman J: Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RCD.Proc Natl Acad Sci USA 95: 5579–5583, 1998

    Google Scholar 

  170. Hohenester E, Sasaki T, Olsen BR, Timpl R: Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution.EMBO J 17: 1656–1664, 1998

    Google Scholar 

  171. Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, William Schnaper H, Pizzo SV: Angiostatin binds ATP synthase on the surface of human endothelial cells.Proc Natl Acad Sci USA 96: 2811–2816, 1999

    Google Scholar 

  172. Sharpe RJ, Byers HR, Scott CF, Bauer SI, Maione TE: Growth inhibition of murine melanoma and human colon carcinoma by recombinant human platelet factor 4.J Natl Cancer Inst 82: 848–853, 1990

    Google Scholar 

  173. Volpert OV, Lawler J, Bouck NP: A human fibrosarcoma inhibits systemic angigenesis and the growth of experimental metastasis via thrombospondin-1.Proc Natl Acad Sci USA 95: 6343–6348, 1998

    Google Scholar 

  174. D'Angelo G, Struman I, Martial J, Weiner RI: Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells in inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin.Proc Natl Acad Sci USA 92: 6374–6378, 1995

    Google Scholar 

  175. Volpert OV, Fong T, Koch AE, Peterson JD, Waltenbaugh C, Tepper RI, Bouck NP: Inhibition of angiogenesis by interleukin 4.J Exp Med 188: 1039–1046, 1998

    Google Scholar 

  176. Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R: TroponinI is present in human cartilage and inhibits angiogenesis.Proc Natl Acad Sci USA 96: 2645–2650, 1999

    Google Scholar 

  177. Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase.J Cell Physiol 160: 194–202, 1994

    Google Scholar 

  178. Aiello LP, Avery R, Arrigg PG, Keyt B, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen MS, Aiello LM, Ferrara N: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.N Engl J Med 331: 1480–1487, 1994

    Google Scholar 

  179. Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E: Hypoxia-induced expression of vascular endothelial growth factor (VEGF) by retinal cells is a common factor in neovascularization.Lab Invest 72: 638–645, 1995

    Google Scholar 

  180. Adamis AP, Shima DT, Tolentino M, Gragoudas ES, Ferrara N, Folkman J, D'Amore PA, Miller JW: Inhibition of VEGF prevents occular neovascularization in a primate.Arch Ophthalmol 114: 66–71, 1996

    Google Scholar 

  181. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGFreceptor chimeric proteins.Proc Natl Acad Sci USA 12: 10457–10461, 1995

    Google Scholar 

  182. Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N: Vascular endothelial growth factor.A cytokine modulating endothelial function in rheumatoid arthritis.J Immunol 152: 4149–4156, 1994

    Google Scholar 

  183. Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF: Vascular permeability factor / vascular endothelial growth factor (VPFNEGF): accumulation and expression in human synovial fluids and rheumatoid arthritis.J Exp Med 180: 340–346, 1994

    Google Scholar 

  184. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF: Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis.J Exp Med 180: 1141–1146, 1994

    Google Scholar 

  185. Brown LF, Harris TJ, Yeo KT, Stahle-Backdahl M, Jackman RW, Berse B, Tognazzi K, Dvorak HF, Detmar M: Increased expression of vascular permaebility factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiforme, and erythema multiforme.J Invest Dermatol 104: 744–749, 1995

    Google Scholar 

  186. Teicher BA, Sotomayor EA, Huang ZD: Anriangiogenic agents potentiate cytotoxic cancer therapies against primary and metastasis disease.Cancer Res 52: 6702–6704, 1992

    Google Scholar 

  187. Teicher BA, Holden SA, Ara G, Korbut T, Memon K: Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma.Cancer Chemother Pharmacol 38: 169–177, 1996

    Google Scholar 

  188. Anderson IC, Shipp MA, Docherty AJ, Teicher BA: Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine Lewis lung carcinoma.Cancer Res 56: 715–718, 1996

    Google Scholar 

  189. Sotomayor EA, Teicher BA, Schwartz GN, Holden SA, Memon K, Herman TS, Frei E: Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo.Cancer Chemother Pharmacol 30: 377–384, 1992

    Google Scholar 

  190. Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff GA, Kufe DW, Weichselbaum RR: Potentiation of the antirumor effect of ionzing radiation by brief concomitant exposures to angiostarin.Cancer Res 58: 5686–5689, 1998

    Google Scholar 

  191. Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Stabs MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW, Weichselbaum RR: Combined effects of angiostatin and ionizing radiation in antitumour therapy.Nature 394: 287–291, 1998

    Google Scholar 

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    Zhenping Zhu & Larry Witte

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Zhu, Z., Witte, L. Inhibition of Tumor Growth and Metastasis by Targeting Tumor-Associated Angiogenesis with Antagonists to the Receptors of Vascular Endothelial Growth Factor. Invest New Drugs 17, 195–212 (1999). https://doi.org/10.1023/A:1006314501634

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