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Angiogenesis in Non-Small Cell Lung Cancer

A New Target for Therapy

  • Leading Article
  • Published:
American Journal of Respiratory Medicine

Abstract

Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development.

Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established.

We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.

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References

  1. Cancer facts and figures [online]. Available from URL: http://www.cancer.org [Accessed 2002 Aug 30]

  2. Ginsberg R, Vokes E, Rosenzweig K. Non-small cell lung cancer. In: DeVita Jr V, Hellman S, Rosenberg S, editors. Cancer: principles and practice of oncology. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001: 925–82

    Google Scholar 

  3. Sherer D, Abulafia O. Angiogenesis during implantation, and placental and early embryonic development. Placenta 2001; 22: 1–13

    Article  PubMed  CAS  Google Scholar 

  4. Folkman J. Angiogenesis in female reproductive organs. In: Alexander N, d’Arcangues C, editors. Steroid hormones and uterine bleeding. Washington, DC: AAAS Press, 1992: 143–58

    Google Scholar 

  5. Nissen N, DiPietro L. Angiogenic mediators in healing wounds. In: Rubanyi G, editor. Angiogenesis in health and disease: basic mechanisms and clinical applications. New York: Marcel Dekker, Inc., 2000: 417–27

    Google Scholar 

  6. Szekanecz Z, Koch A. Angiogenesis in rheumatoid arthritis. In: Rubanyi G, editor. Angiogenesis in health and disease: basic mechanisms and clinical applications. New York: Marcel Dekker, Inc., 2000: 429–50

    Google Scholar 

  7. Nickoloff B, Mitra R, Varani J, et al. Aberrant production of interleukin-8 and thrombospondin-1 by psoriatic keratinocytes mediates angiogenesis. Am J Pathol 1994; 144: 820–8

    PubMed  CAS  Google Scholar 

  8. Ohno-Matsui K, Morita I, Tombran-Tink J, et al. Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 2001; 189: 323–33

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–64

    Article  PubMed  CAS  Google Scholar 

  11. Hobson B, Denekamp J. Endothelial proliferation in tumours and normal tissues: continous labelling studies. Br J Cancer 1984; 49: 405–13

    Article  PubMed  CAS  Google Scholar 

  12. Folkman J. Tumor angiogenesis and tissue factor. Nat Med 1996; 2: 167–8

    Article  PubMed  CAS  Google Scholar 

  13. Rak J, Filmus J, Kerbel R. Reciprocal paracrine interactions between tumour cells and endothelial cells: the ‘angiogenic progression’ hypothesis. Eur J Cancer 1996; 32A: 2438–50

    Article  PubMed  CAS  Google Scholar 

  14. Brooks P. Role of integrins in angiogenesis. Eur J Cancer 1996; 32A: 2423–9

    Article  PubMed  CAS  Google Scholar 

  15. Brooks P, Clark R, Cheresh D. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994; 264: 569–71

    Article  PubMed  CAS  Google Scholar 

  16. Holden SN, Morrow M, O’Bryant C, et al. Correlative biological assays used to guide dose escalation in a phase I study of the antiangiogenic αvβ3 and αvβ5 integrin antagonist EMD 121974 [abstract 110]. Proc Am Soc Clin Oncol 2002; 21: 28a

    Google Scholar 

  17. Koch A, Halloran M, Haskell C, et al. Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 1995; 376: 517–9

    Article  PubMed  CAS  Google Scholar 

  18. Maier J, Delia D, Thorpe P, et al. In vitro inhibition of endothelial cell growth by the antiangiogenic drug AGM-1470 (TNP-470) and the anti-endoglin antibody TEC-11. Anticancer Drugs 1997; 8: 238–44

    Article  PubMed  CAS  Google Scholar 

  19. Cox G, Steward W, O’Byrne K. The plasmin cascade and matrix metalloproteinases in non-small cell lung cancer. Thorax 1999; 54: 169–79

    Article  PubMed  CAS  Google Scholar 

  20. Glass W, Radnik R, Garoni J, et al. Urokinase-dependent adhesion loss and shape change afer cyclic adenosine monophosphate elevation in cultured rat mesangial cells. J Clin Invest 1988; 82: 1992–2000

    Article  PubMed  CAS  Google Scholar 

  21. Andreasen P, Kjoller L, Christensen L, et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1–22

    Article  PubMed  CAS  Google Scholar 

  22. Nagayama M, Sato A, Hayakawa H, et al. Plasminogen activators and their inhibitors in non-small cell lung cancer: low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994; 73: 1398–405

    Article  PubMed  CAS  Google Scholar 

  23. Robert C, Bolon I, Gazzeri S, et al. Expression of plasminogen activator inhibitors 1 and 2 in lung cancer and their role in tumor progression. Clin Cancer Res 1999; 5: 2094–102

    PubMed  CAS  Google Scholar 

  24. Reuning U, Magdolen V, Wilhelm O, et al. Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis. Int J Oncol 1998; 13: 893–906

    PubMed  CAS  Google Scholar 

  25. Pedersen H, Brunner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor and type-1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54: 4671–5

    PubMed  CAS  Google Scholar 

  26. Muchlenweg B, Sperl S, Madolen V, et al. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Expert Opin Biol Ther 2001; 1: 683–91

    Article  Google Scholar 

  27. Nelson A, Fingleton B, Rothenberg M, et al. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000; 18: 1135–49

    PubMed  CAS  Google Scholar 

  28. Hidalgo M, Eckhardt S. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–93

    Article  PubMed  CAS  Google Scholar 

  29. Bolon I, Devouasoux M, Moro R, et al. Expression of urokinase-type plasminogen activator, stromelysin 1, stromelysin 3, and matrilysin genes in lung carcinomas. Am J Pathol 1997; 150: 1619–29

    PubMed  CAS  Google Scholar 

  30. Brown P, Bloxidge R, Stuart N, et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma. J Natl Cancer Inst 1993; 85: 574–8

    Article  PubMed  CAS  Google Scholar 

  31. Nawrocki B, Polette M, Marchand V, et al. Expression of matrix metalloproteinases and their inhibitors in human bronchopulmonary carcinomas: quantificative and morphological analyses. Int J Cancer 1997; 72: 556–64

    Article  PubMed  CAS  Google Scholar 

  32. Tokuraku M, Sato H, Murakami S, et al. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis. Int J Cancer 1995; 64: 355–9

    Article  PubMed  CAS  Google Scholar 

  33. Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275–88

    Article  PubMed  CAS  Google Scholar 

  34. Shing Y, Folkman J, Sullivan R, et al. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 1984; 223: 1296–9

    Article  PubMed  CAS  Google Scholar 

  35. Esch F, Ueno N, Baird A, et al. Primary structure of bovine brain acidic fibroblast growth factor. Biochem Biophys Res Commun 1985; 133: 554–62

    Article  PubMed  CAS  Google Scholar 

  36. Fett J, Strydom D, Lobb R, et al. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 1985; 24: 5480–6

    Article  PubMed  CAS  Google Scholar 

  37. Schreiber A, Winkler M, Derynck R. Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor. Science 1986; 232: 1250–3

    Article  PubMed  CAS  Google Scholar 

  38. Roberts A, Sporn M, Assoian R, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 1986; 83: 4167–71

    Article  PubMed  CAS  Google Scholar 

  39. Frater-Schroder M, Risau W, Hallmann R, et al. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci U S A 1987; 84: 5277–88

    Article  PubMed  CAS  Google Scholar 

  40. Senger D, Galli S, Dvorak A, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–5

    Article  PubMed  CAS  Google Scholar 

  41. Leung D, Cachianes G, Kuang W, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–9

    Article  PubMed  CAS  Google Scholar 

  42. Bussolino F, Wang J, Defilippi P, et al. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 1989; 337: 471–3

    Article  PubMed  CAS  Google Scholar 

  43. Ishikawa F, Miyazono K, Hellman U, et al. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 1989; 338: 557–62

    Article  PubMed  CAS  Google Scholar 

  44. Maglione D, Guerriero V, Viglietto G, et al. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 1991; 88: 9267–71

    Article  PubMed  CAS  Google Scholar 

  45. Koch A, Polverini P, Kunkel S, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992; 258: 1798–801

    Article  PubMed  CAS  Google Scholar 

  46. Fang W, Hartmann N, Chow D, et al. Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. J Biol Chem 1992; 267: 25889–97

    PubMed  CAS  Google Scholar 

  47. Rosen E, Grant D, Kleinman H, et al. Scatter factor (hepatocyte growth factor) is a potent angiogenesis factor in vivo. Symp Soc Exp Biol 1993; 47: 227–34

    PubMed  CAS  Google Scholar 

  48. Jackson D, Volpert O, Bouck N, et al. Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 1994; 266: 1581–4

    Article  PubMed  CAS  Google Scholar 

  49. Suri C, Jones P, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996; 87: 1171–80

    Article  PubMed  CAS  Google Scholar 

  50. Kozian D, Ziehe M, Augustin H. The activin-binding protein follistatin regulates autocrine endothelial cell activity and induces angiogenesis. Lab Invest 1997; 76: 267–76

    PubMed  CAS  Google Scholar 

  51. Sierra-Honigmann M, Nath A, Murakami C, et al. Biological action of leptin as an angiogenic factor. Science 1998; 281: 1683–6

    Article  PubMed  CAS  Google Scholar 

  52. Dvorak H, Brown L, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995; 146: 1029–39

    PubMed  CAS  Google Scholar 

  53. Nor J, Christensen J, Mooney D, et al. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 1999; 154: 375–84

    Article  PubMed  CAS  Google Scholar 

  54. Unemori E, Ferrara N, Bauer E, et al. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992; 153: 557–62

    Article  PubMed  CAS  Google Scholar 

  55. Mandriota S, Seghezzi G, Vassalli J, et al. Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 1995; 270: 9709–16

    Article  PubMed  CAS  Google Scholar 

  56. Pepper M, Ferrera N, Orci L, et al. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor type 1 in microvascular endothelial cells. Biochem Biophys Res Commun 1991; 181: 902–6

    Article  PubMed  CAS  Google Scholar 

  57. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359: 843–5

    Article  PubMed  CAS  Google Scholar 

  58. Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13: 9–22

    PubMed  CAS  Google Scholar 

  59. Rak J, Mitsuhashi Y, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995; 55: 4575–80

    PubMed  CAS  Google Scholar 

  60. Kieser A, Welch H, Brandner G, et al. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 1994; 9: 963–9

    PubMed  CAS  Google Scholar 

  61. Senger D, Van de Water L, Brown L, et al. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 1993; 12: 303–24

    Article  PubMed  CAS  Google Scholar 

  62. Yuan A, Yu C, Kuo S, et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 2001; 19: 432–41

    PubMed  CAS  Google Scholar 

  63. Bork P, Downing K, Kieffer B, et al. Structure and distribution of modules in extracellular proteins. Q Rev Biophysics 1996; 29: 119–67

    Article  CAS  Google Scholar 

  64. de Vries C, Escobedo J, Ueno H, et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989–91

    Article  PubMed  Google Scholar 

  65. Terman B, Dougher-Vermazen M, Carrion M, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187: 1579–86

    Article  PubMed  CAS  Google Scholar 

  66. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182–6

    Article  PubMed  CAS  Google Scholar 

  67. Ezekowitz R, Mulliken J, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992; 326: 1456–63

    Article  PubMed  CAS  Google Scholar 

  68. The Angiogenesis Foundation [online]. Available from URL: http://www.angio.org [Accessed 2002 Aug 30]

  69. Sidky Y, Borden E. Inhibition of angiogenesis by interferons: effects on tumorand lymphocyte-induced vascular responses. Cancer Res 1987; 47: 5155–61

    PubMed  CAS  Google Scholar 

  70. Friesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation by gamma-interferon. J Cell Biol 1987; 104: 689–96

    Article  PubMed  CAS  Google Scholar 

  71. Docherty A, Lyons A, Smith B, et al. Sequence of human tissue inhibitor of metalloprotinases and its identity to erythroid-potentiating activity. Nature 1985; 318: 66–8

    Article  PubMed  CAS  Google Scholar 

  72. Stetler-Stevenson W, Krutzsch H, Liotta L. Tissue inhibitor of metalloproteinase (TIMP-2). J Biol Chem 1989; 264: 17374–8

    PubMed  CAS  Google Scholar 

  73. Apte S, Mattei M, Olsen B. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 1994; 19: 86–90

    Article  PubMed  CAS  Google Scholar 

  74. Olson T, Hirohata S, Ye J, et al. Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and TIMP4 genes to human chromosome 3p25 and mouse chromosome 6, respectively. Genomics 1998; 51: 148–51

    Article  PubMed  CAS  Google Scholar 

  75. Sato Y, Abe M, Takaki R. Platelet factor 4 blocks the binding of basic fibroblast growth factor to the receptor and inhibits the spontaneous migration of vascular endothelial cells. Biochem Biophys Res Commun 1990; 172: 595–600

    Article  PubMed  CAS  Google Scholar 

  76. Iruela-Arispe M. Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc Natl Acad Sci U S A 1991; 88: 5026–30

    Article  PubMed  CAS  Google Scholar 

  77. Ferrara N, Clapp C, Weiner R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 1991; 129: 896–900

    Article  PubMed  CAS  Google Scholar 

  78. O’Reilly M, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–28

    Article  PubMed  Google Scholar 

  79. Voest E, Kenyon B, O’Reilly M, et al. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995; 87: 581–6

    Article  PubMed  CAS  Google Scholar 

  80. O’Reilly M, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–85

    Article  PubMed  Google Scholar 

  81. Maisonpierre P, Suri C, Jones P, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55–60

    Article  PubMed  CAS  Google Scholar 

  82. Pike S, Yao L, Jones K, et al. Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J Exp Med 1998; 188: 2349–56

    Article  PubMed  CAS  Google Scholar 

  83. Vazquez F, Hastings G, Ortega M, et al. METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J Biol Chem 1999; 274: 23349–57

    Article  PubMed  CAS  Google Scholar 

  84. Dawson D, Volpert O, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999; 285: 245–8

    Article  PubMed  CAS  Google Scholar 

  85. Fortier A, Nelson B, Grella D, et al. Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst 1999; 91: 1635–40

    Article  PubMed  CAS  Google Scholar 

  86. O’Reilly M, Pirie-Shepherd S, Lane W, et al. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285: 1926–8

    Article  PubMed  Google Scholar 

  87. Moses M, Wiederschain D, Wu I, et al. Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A 1999; 96: 2645–50

    Article  PubMed  CAS  Google Scholar 

  88. Streit M, Riccardi L, Velasco P, et al. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci U S A 1999; 96: 14888–593

    Article  PubMed  CAS  Google Scholar 

  89. Zhai Y, Ni J, Jiang G, et al. VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo. FASEB J 1999; 13: 181–9

    PubMed  CAS  Google Scholar 

  90. Kamphaus G, Colorado P, Panka D, et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem 2000; 275: 1209–15

    Article  PubMed  CAS  Google Scholar 

  91. Liu N, Lapcevich R, Underhill C, et al. Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth. Cancer Res 2001; 61: 1022–8

    PubMed  CAS  Google Scholar 

  92. O’Reilly M, Holmgren L, Chen C, et al. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689–92

    Article  PubMed  Google Scholar 

  93. Volm M, Mattern J, Koomagi R. Angiostatin expression in non-small cell lung cancer. Clin Cancer Res 2000; 6(8): 3236–40

    PubMed  CAS  Google Scholar 

  94. DeMoraes E, Fogler W, Grant D, et al. Recombinant human angiostatin: a phase I clinical trial assessing safety, pharmacokinetics and pharmacodynamics [abstract no. 10]. Proc Am Soc Clin Oncol 2001; 20: 3a

    Google Scholar 

  95. Boehm T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390: 404–7

    Article  PubMed  CAS  Google Scholar 

  96. New drugs for cancer therapy. Proceedings of the 11 th NCI-EORTC-AACR Symposium; 2000 Nov 9; Amsterdam

  97. Ingber D, Fujita T, Kishimoto S, et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 1990; 348: 555–7

    Article  PubMed  CAS  Google Scholar 

  98. Milkowski D, Weiss R. TNP-470: preclinical and clinical development. In: Voest E, D’Amore P, editors. Tumor angiogenesis and microcirculation. New York: Marcel Dekker, Inc., 2001: 431–47

    Google Scholar 

  99. Satoh H, Ishikawa H, Fujimoto M, et al. Combined effects of TNP-470 and taxol in human non-small cell lung cancer cell lines. Anticancer Res 1998; 18: 1027–30

    PubMed  CAS  Google Scholar 

  100. Herbst R, Tran H, Madden T, et al. Phase I study of the angiogenesis inhibitor TNP-470 in combination of paclitaxel in patients with solid tumors [abstract no. 707]. Proc Am Soc Clin Oncol 2000; 19: 182a

    Google Scholar 

  101. Tran H, Blumenschein JGL, Madden T, et al. Phase I study of the angiogenesis inhibitor TNP-470 in combination with paclitaxel and carboplatin in patients with solid tumors [abstract no. 394]. Proc Am Soc Clin Oncol 2001; 20: 99a

    Google Scholar 

  102. Schultz R, Silberman S, Persky B, et al. Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. Cancer Res 1988; 48: 5539–45

    PubMed  CAS  Google Scholar 

  103. Alvarez O, Carmichael D, DeClerck Y. Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 1990; 82: 589–95

    Article  PubMed  CAS  Google Scholar 

  104. Blavier L, Henriet P, Imren S, et al. Tissue inhibitors of matrix metalloproteinases in cancer. Ann N Y Acad Sci 1999; 878: 108–19

    Article  PubMed  CAS  Google Scholar 

  105. Wojtowicz-Praga S, Torri J, Johnson M, et al. Phase I trial of marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 1998; 16: 2150–6

    PubMed  CAS  Google Scholar 

  106. Shepherd F, Giaccone G, Debruyne C, et al. Randomized double-blind placebocontrolled trial of marimastat in patients with small cell lung cancer following response to first-line chemotherapy: an NCIC-CTG and EORTC study [abstract no. 11]. Proc Am Soc Clin Oncol 2001; 20: 4a

    Google Scholar 

  107. Anderson I, Supko J, Eder J. Pilot pharmacokinetic study of marimastat in combination with carboplatin/paclitaxel in patients with metastatic or locally advanced inoperable non-small cell lung cancer [abstract 719]. Proc Am Soc Clin Oncol 1999; 18: 187a

    Google Scholar 

  108. Gingras D, Renaud A, Mousseau N, et al. Matrix proteinase inhibition by AE-941, a multifunctional anti-angiogenic compound. Anticancer Res 2001; 21: 145–55

    PubMed  CAS  Google Scholar 

  109. Falardeau P, Champagne P, Poyet P, et al. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 2001; 28: 620–5

    Article  PubMed  CAS  Google Scholar 

  110. Hurwitz H, Humphrey J, Williams K, et al. A phase I trial of BMS-275291: a novel, non-hydroxamate, sheddase-sparing matrix metalloproteinase inhibitor with no dose-limiting arthritis [abstract no. 387]. Proc Am Soc Clin Oncol 2001; 20: 98a

    Google Scholar 

  111. Smylie M, Mercier R, Aboulafia D, et al. Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat in patients having advanced non-small cell lung cancer (NSCLC) [abstract no. 1226]. Proc Am Soc Clin Oncol 2001; 20: 307a

    Google Scholar 

  112. Rowinsky E, Humphrey R, Hammond L, et al. Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies. J Clin Oncol 2000; 18: 178–86

    PubMed  CAS  Google Scholar 

  113. Levitt N, Eskens F, O’Byrne K, et al. Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer. Clin Cancer Res 2001; 7: 1912–22

    PubMed  CAS  Google Scholar 

  114. Asano M, Yukita A, Suzuki H. Wide spectrum of antitumor activity of a neutralizing monoclonal antibody to human vascular endothelial growth factor. Jpn J Cancer Res 1999; 90: 93–100

    Article  PubMed  CAS  Google Scholar 

  115. Presta L, Chen H, O’Connor S, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997; 57: 4593–9

    PubMed  CAS  Google Scholar 

  116. Gordon M, Margolin M, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19: 843–50

    PubMed  CAS  Google Scholar 

  117. DeVore R, Fehrenbacher L, Herbst R, et al. A randomized phase II trial comparing Rhumab VEGF plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIb/IV NSCLC [abstract no. 1896]. Proc Am Soc Clin Oncol 2000; 19: 485a

    Google Scholar 

  118. Rosen L. VEGF inhibition: semaxanib (SU5416) — from concept to clinical use. Proceedings of the Third European Congress on Perspectives in Colorectal Cancer; 2001; Dublin, Ireland

  119. Laird A, Vajkoczy P, Shawver L, et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000; 60: 4152–60

    PubMed  CAS  Google Scholar 

  120. Ning S, Laird D, Cherrington J, et al. The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Radiat Res 2002; 157: 45–51

    Article  PubMed  CAS  Google Scholar 

  121. Rosen L, Rosen P, Kabbinavar F, et al. Phase I experience with SU6668, a novel multiple receptor tyrosine kinase inhibibitor in patients with advanced malignancies [abstract no. 383]. Proc Am Soc Clin Oncol 2001; 20: 97a

    Google Scholar 

  122. Mendel DB, Laird AD, Xin X, et al. Development of a preclinical pharmacokinetic/pharmacodynamic relationship for the angiogenesis inhibitor SU11248, a selective inhibitor of VEGF and PDGF receptor tyrosine kinases in clinical development [abstract 94]. Proc Am Soc Clin Oncol 2002; 21: 24a

    Google Scholar 

  123. Sugen [online]. Available from URL: http://www.sugen.com [Accessed 2002 Aug 30]

  124. D’Amato R. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 4082–5

    Article  PubMed  Google Scholar 

  125. Merchant J, Hammes L, Larson M, et al. Pilot and safety trial of carboplatin, paclitaxel and thalidomide in advanced non-small cell lung cancer [abstract no. 2130]. Proc Am Soc Clin Oncol 2000; 19: 541a

    Google Scholar 

  126. Marriott J, Muller G, Stirling D, et al. Immunotherapeutic and antitumour potential of thalidomide analogues. Expert Opin Biol Ther 2001; 1: 675–82

    Article  PubMed  CAS  Google Scholar 

  127. Schiller J, Bittner G. Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization. Clin Cancer Res 1999; 5: 4287–94

    PubMed  CAS  Google Scholar 

  128. Williams J, Weitman S, Gonzalez C, et al. Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies. Clin Cancer Res 2001; 7: 724–33

    PubMed  CAS  Google Scholar 

  129. Kalidas M, Hammond L, Patnaik A, et al. A phase I and pharmacokinetic study of the angiogenesis inhibitor, squalamine lactate (MSI-1256F) [Abstract no. 698]. Proc Am Soc Clin Oncol 2000; 19: 180a

    Google Scholar 

  130. Schiller J, Hammond L, Carbone D, et al. Phase 2A trial of squalamine for treatment of advanced non-small cell lung cancer [abstract 1353]. Proc Am Soc Clin Oncol 2001; 20: 339a

    Google Scholar 

  131. Kohn E, Felder C, Jacobs W, et al. Structure function analysis of signal and growth inhibition by carboxyamido-triazole, CAI. Cancer Res 1994; 54: 935–42

    PubMed  CAS  Google Scholar 

  132. Kohn E, Alessandro R, Spoonster J, et al. Angiogenesis: role of calcium-mediated signal transduction. Proc Natl Acad Sci U S A 1995; 92: 1307–11

    Article  PubMed  CAS  Google Scholar 

  133. Kohn E, Reed E, Sarosy G, et al. Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. Cancer Res 1996; 56: 569–73

    PubMed  CAS  Google Scholar 

  134. Kohn E, Reed E, Sarosy G, et al. A phase 1 trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction. Clin Cancer Res 2001; 7: 1600–9

    PubMed  CAS  Google Scholar 

  135. Weidner N, Semple J, Welch W, et al. Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1–8

    Article  PubMed  CAS  Google Scholar 

  136. Gasparini G, Harris A. Prognostic significance of tumor vascularity. In: Teicher B, editor. Antiangiogenic agents in cancer therapy. Totowa: Humana Press, 1999: 317–40

    Google Scholar 

  137. Vermeulen P, Gasparini G, Fox S, et al. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996; 32A: 2474–84

    Article  PubMed  CAS  Google Scholar 

  138. Macchiarini P, Fontanini G, Hardin J, et al. Relation of neovascularization to metastasis of non-small-cell lung cancer. Lancet 1992; 340: 145–6

    Article  PubMed  CAS  Google Scholar 

  139. Pastorino U, Andreola S, Taglibue E, et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J Clin Oncol 1997; 15: 2858–65

    PubMed  CAS  Google Scholar 

  140. Giatromanolaki A, Koukourakis A, O’Byrne K, et al. Prognostic value of angiogenesis in operable non-small cell lung cancer. J Pathol 1996; 179: 80–8

    Article  PubMed  CAS  Google Scholar 

  141. Apolinario R, van der Valk P, de Jong J, et al. Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J Clin Oncol 1997; 15: 2456–66

    PubMed  CAS  Google Scholar 

  142. Fontanini G, Lucchi M, Vignati S, et al. Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J Natl Cancer Inst 1997; 89: 881–6

    Article  PubMed  CAS  Google Scholar 

  143. Angeletti C, Lucchi M, Fontanini G, et al. Prognostic significance of tumoral angiogenesis in completely resected late stage lung carcinoma (stage IIIA-N2). Impact of adjuvant therapies in a subset of patients at high risk of recurrence. Cancer 1996; 78: 409–15

    Article  PubMed  CAS  Google Scholar 

  144. Tanaka F, Otake Y, Yanagihara K, et al. Evaluation of angiogenesis in non-small cell lung cancer: comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res 2001; 7: 3410–5

    PubMed  CAS  Google Scholar 

  145. Fox S, Leek R, Weekes M. Quantification and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chaulkley count and computer image analysis. J Pathol 1995; 177: 275–83

    Article  PubMed  CAS  Google Scholar 

  146. Anderson H, Price P, Blomley M, et al. Measuring changes in human tumour vasculature in response to therapy using functional imaging techniques. Br J Cancer 2001; 85: 1085–93

    Article  PubMed  CAS  Google Scholar 

  147. Padhani A, Neeman M. Challenges for imaging angiogenesis. Br J Radiol 2001; 74: 886–90

    PubMed  CAS  Google Scholar 

  148. Wild R, Ramakrishnan S, Sedgewick J, et al. Quantitative assessment of angiogenesis and tumor vessel architecture by computer-assisted digital image analysis: effects of VEGF-toxin conjugate on tumor microvessel density. Microvasc Res 2000; 59: 368–76

    Article  PubMed  CAS  Google Scholar 

  149. Guo L, Burke P, Lo S, et al. Quantitative analysis of angiogenesis using confocal lase scanning microscopy. Angiogenesis 2001; 4: 187–91

    Article  PubMed  CAS  Google Scholar 

  150. Iizasa T, Fujisawa T, Suzuki M, et al. Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin Cancer Res 1999; 5: 149–53

    PubMed  CAS  Google Scholar 

  151. Nguyen M, Watanabe H, Budson A, et al. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 1994; 86: 356–61

    Article  PubMed  CAS  Google Scholar 

  152. Takigawa N, Segawa Y, Fujimoto N, et al. Elevated vascular endothelial growth factor levels in sera of patients with lung cancer. Anticancer Res 1998; 18: 1251–4

    PubMed  CAS  Google Scholar 

  153. Ueno K, Inoue Y, Kawaguchi T, et al. Increased serum levels of basic fibroblast growth factor in lung cancer patients: relevance to response of therapy and prognosis. Lung Cancer 2001; 31: 213–9

    Article  PubMed  CAS  Google Scholar 

  154. Poon R, Fan S, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001; 19: 1207–25

    PubMed  CAS  Google Scholar 

  155. Stadler W, Ratain M. Development of target-based antineoplastic agents. Invest New Drugs 2000; 18: 7–16

    Article  PubMed  CAS  Google Scholar 

  156. Millar A, Brown P, Moore J, et al. Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Br J Clin Pharmacol 1998; 45: 21–6

    Article  PubMed  CAS  Google Scholar 

  157. Amery W, Dony J. A clinical trial design avoiding undue placebo treatment. J Clin Pharmacol 1975; 15: 674–9

    PubMed  CAS  Google Scholar 

  158. Kopec J, Abramhamowicz M, Esdaile J. Randomized discontinuation trials: utility and efficiency. J Clin Epidemiol 1993; 46: 959–71

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the Public Health Service, National Cancer Institute (CA 16359 and CA 75588).

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Correspondence to Tracy E. Kim.

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Kim, T.E., Murren, J.R. Angiogenesis in Non-Small Cell Lung Cancer. Am J Respir Med 1, 325–338 (2002). https://doi.org/10.1007/BF03256626

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