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Challenges for patient selection with VEGF inhibitors

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Abstract

As targeted therapies for cancer become increasingly integrated into standard practice, appropriate selection of the patients most likely to benefit from these therapies is now receiving critical scrutiny. Early experience with therapies directed at targets that are definitively overactive (e.g. the bcr-abl tyrosine kinase targeted by imatinib) or over-expressed [e.g. the human epidermal growth factor receptor 2 (HER2) targeted by trastuzumab] has generated the perception that pre-treatment target assessment is a pre-requisite for therapy with all targeted agents. However, emerging evidence suggests that this is not presently feasible for anti-angiogenic agents. Despite considerable evidence for the association of intratumoral and/or plasma vascular endothelial growth factor (VEGF) levels with tumor progression and/or poor prognosis, pre-treatment VEGF levels do not appear to be predictive of response to anti-angiogenic therapy. This may possibly be due to the complexity of the angiogenic pathways and the limitations associated with current methods of VEGF detection and quantification; e.g. low assay sensitivity and lack of standardized methods could prevent detection of very small increases in VEGF, which may be clinically important in patients with tumors that are highly dependent on this growth factor. In addition to a general lack of agreement as to the relative clinical relevance of circulating versus tumor VEGF levels, the absence of a ‘gold standard’ VEGF detection assay and the lack of a predefined, clinically relevant cut-off pose a significant hindrance to the clinical utility of VEGF measurements for therapy selection. Given the fundamental importance of angiogenesis for tumor growth and progression, and the key role of VEGF in these processes, presently it seems appropriate to view anti-VEGF agents such as bevacizumab (Avastin®) as having potential utility, independently of pre-treatment screening. Further research is needed to define the relationship between potential surrogate markers of VEGF pathway activity and clinical outcomes.

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References

  1. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18

    PubMed  CAS  Google Scholar 

  2. Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3:643–651

    PubMed  CAS  Google Scholar 

  3. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  PubMed  CAS  Google Scholar 

  4. Jain RK (2002) Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 29:3–9

    PubMed  CAS  Google Scholar 

  5. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611

    PubMed  CAS  Google Scholar 

  6. Hicklin DJ, Ellis LM (2004) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    PubMed  Google Scholar 

  7. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    PubMed  CAS  Google Scholar 

  8. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch Nat Rev Cancer 3:401–410

    PubMed  CAS  Google Scholar 

  9. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    PubMed  CAS  Google Scholar 

  10. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368–4380

    PubMed  CAS  Google Scholar 

  11. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611

    PubMed  CAS  Google Scholar 

  12. Shibuya M (2001) Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct 26:25–35

    PubMed  CAS  Google Scholar 

  13. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    PubMed  CAS  Google Scholar 

  14. Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865

    PubMed  CAS  Google Scholar 

  15. Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280:C1358–C1366

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  17. Park JE, Keller GA, Ferrara N (1993) The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4:1317–1326

    PubMed  CAS  Google Scholar 

  18. Mignatti P, Tsuboi R, Robbins E, Rifkin DB (1989) In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases. J Cell Biol 108:671–682

    PubMed  CAS  Google Scholar 

  19. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    PubMed  CAS  Google Scholar 

  20. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506

    PubMed  CAS  Google Scholar 

  21. Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156(3):965–976

    PubMed  CAS  Google Scholar 

  22. Brogi E, Schatterman G, Wu T, Kim EA, Varticoski L, Keyt B, Isner JM (1996) Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest 97(2):469–476

    PubMed  CAS  Google Scholar 

  23. Kremer C, Breier G, Risau W, Plate KH (1997) Up-regulation of flk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system. Cancer Res 57(17):3852–3859

    PubMed  CAS  Google Scholar 

  24. Shen BQ, Lee DY, Gerber HP, Keyt BA, Ferrara N, Zioncheck TF (1998) Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. J Biol Chem 273(45):29979–29985

    PubMed  CAS  Google Scholar 

  25. Asano M, Yukita A, Matsumoto T, Kondo S, Suzuki H (1995) Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. Cancer Res 55:5296–5301

    PubMed  CAS  Google Scholar 

  26. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    PubMed  CAS  Google Scholar 

  27. Gasparini G, Longo R, Toi M, Ferrara N (2005). Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat Clin Pract Oncol 2:562–577

    PubMed  CAS  Google Scholar 

  28. Bergsland E, Dickler MN (2004) Maximizing the potential of bevacizumab in cancer treatment. Oncologist 9(Suppl 1):36–42

    PubMed  CAS  Google Scholar 

  29. Baluk P, Hashizume H, McDonald DM (2005) Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 15:102–111

    PubMed  CAS  Google Scholar 

  30. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845

    PubMed  CAS  Google Scholar 

  31. Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848

    PubMed  CAS  Google Scholar 

  32. Cascinu S, Graziano F, Catalano V, Staccioli MP, Barni S, Giordani P, Rossi MC, Baldelli AM, Muretto P, Valenti A, Catalano G (2000) Differences of vascular endothelial growth factor (VEGF) expression between liver and abdominal metastases from colon cancer. Implications for the treatment with VEGF inhibitors. Clin Exp Metastasis 18:651–655

    PubMed  CAS  Google Scholar 

  33. Gadducci A, Viacava P, Cosio S, Cecchetti D, Fanelli G, Fanucchi A, Teti G, Genazzani AR (2003) Vascular endothelial growth factor (VEGF) expression in primary tumors and peritoneal metastases from patients with advanced ovarian carcinoma. Anticancer Res 23:3001–3008

    PubMed  CAS  Google Scholar 

  34. Werther K, Christensen IJ, Nielsen HJ (2002a) Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets. Scand J Clin Lab Invest 62:343–350

    CAS  Google Scholar 

  35. Kusumanto YH, Dam WA, Hospers GA, Meijer C, Mulder NH (2003) Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis 6:283–287

    PubMed  CAS  Google Scholar 

  36. George ML, Eccles SA, Tutton MG, Abulafi AM, Swift RI (2000) Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging? Clin Cancer Res 6:3147–3152

    PubMed  CAS  Google Scholar 

  37. Salven P, Orpana A, Joensuu H (1999) Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res 5:487–491

    PubMed  CAS  Google Scholar 

  38. Poon RTP, Lau CP, Cheung ST, Yu WC, Fan ST (2003) Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Res 63:3121–3126

    PubMed  CAS  Google Scholar 

  39. Werther K, Christensen IJ, Nielsen HJ (2002b) Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. Br J Cancer 86:417–423

    CAS  Google Scholar 

  40. Jelkmann W (2001) Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem 47:617–623

    PubMed  CAS  Google Scholar 

  41. Karayiannakis AJ, Bolanaki H, Syrigos KN, Asimakopoulos B, Polychronidis A, Anagnostoulis S, Simopoulos C (2003) Serum vascular endothelial growth factor levels in pancreatic cancer patients correlate with advanced and metastatic disease and poor prognosis. Cancer Lett 194:119–124

    PubMed  CAS  Google Scholar 

  42. Jacobsen J, Grankvist K, Rasmuson T, Bergh A, Landberg G, Ljungberg B (2004) Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int 93:297–302

    PubMed  CAS  Google Scholar 

  43. Koukourakis MI, Giatromanolaki A, Thorpe PE, Brekken RA, Sivridis E, Kakolyris S, Georgoulias V, Gatter KC, Harris AL (2000) Vascular endothelial growth factor/KDR activated microvessel density versus CD31 standard microvessel density in non-small cell lung cancer. Cancer Res 60:3088–3095

    PubMed  CAS  Google Scholar 

  44. Inoue K, Slaton JW, Karashima T, Yoshikawa C, Shuin T, Sweeney P, Millikan R, Dinney CP (2000) The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Clin Cancer Res 6:4866–4873

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  46. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP (1996) Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56:2013–2016

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  49. Amaya H, Tanigawa N, Lu C, Matsumura M, Shimomatsuya T, Horiuchi T, Muraoka R (1997) Association of vascular endothelial growth factor expression with tumor angiogenesis, survival and thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in human colorectal cancer. Cancer Lett 119:227–235

    PubMed  CAS  Google Scholar 

  50. Wong MP, Cheung N, Yuen ST, Leung SY, Chung LP (1999) Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer 81:845–850

    PubMed  CAS  Google Scholar 

  51. Eisma RJ, Spiro JD, Kreutzer DL (1997) Vascular endothelial growth factor expression in head and neck squamous cell carcinoma. Am J Surg 174:513–517

    PubMed  CAS  Google Scholar 

  52. Suzuki K, Hayashi N, Miyamoto Y, Yamamoto M, Ohkawa K, Ito Y, Sasaki Y, Yamaguchi Y, Nakase H, Noda K, Enomoto N, Arai K, Yamada Y, Yoshihara H, Tujimura T, Kawano K, Yoshikawa K, Kamada T (1996) Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 56:3004–3009

    PubMed  CAS  Google Scholar 

  53. O’Byrne KJ, Koukourakis MI, Giatromanolaki A, Cox G, Turley H, Steward WP, Gatter K, Harris AL (2000) Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer 82:1427–1432

    PubMed  CAS  Google Scholar 

  54. Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR, Smith SK (1995) Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst 87:506–516

    PubMed  CAS  Google Scholar 

  55. Toi M, Matsumoto T, Bando H (2001) Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2:667–673

    PubMed  CAS  Google Scholar 

  56. Jacobsen J, Rasmuson T, Grankvist K, Ljungberg B (2000) Vascular endothelial growth factor as prognostic factor in renal cell carcinoma. J Urol 163:343–347

    PubMed  CAS  Google Scholar 

  57. Chow NH, Liu HS, Chan SH, Cheng HL, Tzai TS (1999) Expression of vascular endothelial growth factor in primary superficial bladder cancer. Anticancer Res 19:4593–4597

    PubMed  CAS  Google Scholar 

  58. Abdulrauf SI, Edvardsen K, Ho KL, Yang XY, Rock JP, Rosenblum ML (1998) Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma. J Neurosurg 88:513–520

    Article  PubMed  CAS  Google Scholar 

  59. Yao Y, Kubota T, Sato K, Kitai R, Takeuchi H, Arishima H (2001) Prognostic value of vascular endothelial growth factor and its receptors Flt-1 and Flk-1 in astrocytic tumours. Acta Neurochir (Wien) 143:159–166

    CAS  Google Scholar 

  60. Zhou YH, Tan F, Hess KR, Yung WK (2003) The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res 9:3369–3375

    PubMed  CAS  Google Scholar 

  61. Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki H, Tominaga T (1997) Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 89:139–147

    PubMed  CAS  Google Scholar 

  62. Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor b-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57:963–969

    PubMed  CAS  Google Scholar 

  63. Eppenberger U, Kueng W, Schlaeppi JM, Roesel JL, Benz C, Mueller H, Matter A, Zuber M, Luescher K, Litschgi M, Schmitt M, Foekens JA, Eppenberger-Castori S (1998) Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 16:3129–3136

    PubMed  CAS  Google Scholar 

  64. Linderholm B, Tavelin B, Grankvist K, Henriksson R (1998) Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 16:3121–3128

    PubMed  CAS  Google Scholar 

  65. Gasparini G, Toi M, Miceli R, Vermeulen PB, Dittadi R, Biganzoli E, Morabito A, Fanelli M, Gatti C, Suzuki H, Tominaga T, Dirix LY, Gion M (1999) Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 5:101–111

    PubMed  CAS  Google Scholar 

  66. Linderholm B, Lindh B, Tavelin B, Grankvist K, Henriksson R (2000) p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma. Int J Cancer 89:51–62

    PubMed  CAS  Google Scholar 

  67. Linderholm BK, Lindh B, Beckman L, Erlanson M, Edin K, Travelin B, Bergh J, Grankvist K, Henriksson R (2003) Prognostic correlation of basic fibroblast growth factor and vascular endothelial growth factor in 1307 primary breast cancers. Clin Breast Cancer 4:340–347

    Article  PubMed  CAS  Google Scholar 

  68. Bando H, Weich HA, Brokelmann M, Horiguchi S, Funata N, Ogawa T, Toi M (2005) Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer. Br J Cancer 92:553–561

    PubMed  CAS  Google Scholar 

  69. Toi M, Inada K, Suzuki H, Tominaga T (1995) Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36:193–204

    PubMed  CAS  Google Scholar 

  70. Linderholm BK, Lindahl T, Holmberg L, Klaar S, Lennerstrand J, Henriksson R, Bergh J (2001) The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer. Cancer Res 61:2256–2260

    PubMed  CAS  Google Scholar 

  71. Obermair A, Kucera E, Mayerhofer K, Speiser P, Seifert M, Czerwenka K, Kaider A, Leodolter S, Kainz C, Zeillinger R (1997) Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int J Cancer 74:455–458

    PubMed  CAS  Google Scholar 

  72. Bachelot T, Ray-Coquard I, Menetrier-Caux C, Rastkha M, Duc A, Blay JY (2003) Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 88:1721–1726

    PubMed  CAS  Google Scholar 

  73. Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CM (2000) Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer 83:620–625

    PubMed  CAS  Google Scholar 

  74. Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, Mori A, Onodera H, Imamura M (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78:1379–1384

    PubMed  CAS  Google Scholar 

  75. Maeda K, Nishiguchi Y, Yashiro M, Yamada S, Onoda N, Sawada T, Kang SM, Hirakawa K (2000) Expression of vascular endothelial growth factor and thrombospondin-1 in colorectal carcinoma. Int J Mol Med 5:373–378

    PubMed  CAS  Google Scholar 

  76. Harada Y, Ogata Y, Shirouzu K (2001) Expression of vascular endothelial growth factor and its receptor KDR (kinase domain-containing receptor)/Flk-1 (fetal liver kinase-1) as prognostic factors in human colorectal cancer. Int J Clin Oncol 6:221–228

    PubMed  CAS  Google Scholar 

  77. Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77:998–1002

    PubMed  CAS  Google Scholar 

  78. Zheng S, Han MY, Xiao ZX, Peng JP, Dong Q (2003) Clinical significance of vascular endothelial growth factor expression and neovascularization in colorectal carcinoma. World J Gastroenterol 9:1227–1230

    PubMed  Google Scholar 

  79. Giatromanolaki A, Sivridis E, Brekken R, Thorpe PE, Anastasiadis P, Gatter KC, Harris AL, Koukourakis MI (2001) The angiogenic “vascular endothelial growth factor/flk-1(KDR) receptor” pathway in patients with endometrial carcinoma: prognostic and therapeutic implications. Cancer 92:2569–2577

    PubMed  CAS  Google Scholar 

  80. Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:858–863

    PubMed  CAS  Google Scholar 

  81. Saito H, Tsujitani S, Kondo A, Ikeguchi M, Maeta M, Kaibara N (1999) Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma. Surgery 125:195–201

    PubMed  CAS  Google Scholar 

  82. Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G, Simopoulos C, Karatzas G (2002) Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236:37–42

    PubMed  Google Scholar 

  83. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T (1997) Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol 15:826–832

    PubMed  CAS  Google Scholar 

  84. Mineta H, Miura K, Ogino T, Takebayashi S, Misawa K, Ueda Y, Suzuki I, Dictor M, Borg A, Wennerberg J (2000) Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer 83:775–781

    PubMed  CAS  Google Scholar 

  85. Smith BD, Smith GL, Carter D, Sasaki CT, Haffty BG (2000) Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 18:2046–2052

    PubMed  CAS  Google Scholar 

  86. Salven P, Heikkila P, Anttonen A, Kajanti M, Joensuu H (1997) Vascular endothelial growth factor in squamous cell head and neck carcinoma: expression and prognostic significance. Mod Pathol 10:1128–1133

    PubMed  CAS  Google Scholar 

  87. De Schutter H, Landuyt W, Verbeken E, Goethals L, Hermans R, Nuyts S (2005) The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/–chemotherapy. BMC Cancer 5:42

    PubMed  Google Scholar 

  88. Fontanini G, Vignati S, Boldrini L, Chine S, Silvestri V, Lucchi M, Mussi A, Angeletti CA, Bevilacqua G (1997) Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res 3:861–865

    PubMed  CAS  Google Scholar 

  89. Volm M, Koomagi R, Mattern J (1997) Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer 74:64–68

    PubMed  CAS  Google Scholar 

  90. Imoto H, Osaki T, Taga S, Ohgami A, Ichiyoshi Y, Yasumoto K (1998) Vascular endothelial growth factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc Surg 115:1007–1014

    PubMed  CAS  Google Scholar 

  91. Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (2001) 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 19:432–441

    PubMed  CAS  Google Scholar 

  92. Kaya A, Ciledag A, Gulbay BE, Poyraz BM, Celik G, Sen E, Savas H, Savas I (2004) The prognostic significance of vascular endothelial growth factor levels in sera of non-small cell lung cancer patients. Respir Med 98:632–636

    PubMed  Google Scholar 

  93. Fontanini G, Faviana P, Lucchi M, Boldrini L, Mussi A, Camacci T, Mariani MA, Angeletti CA, Basolo F, Pingitore R (2002) A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma. Br J Cancer 86:558–563

    PubMed  CAS  Google Scholar 

  94. Shimanuki Y, Takahashi K, Cui R, Hori S, Takahashi F, Miyamoto H, Fukurchi Y (2005) Role of serum vascular endothelial growth factor in the prediction of angiogenesis and prognosis for non-small cell lung cancer. Lung 183:29–42

    PubMed  CAS  Google Scholar 

  95. Ugurel S, Rappl G, Tilgen W, Reinhold U (2001) Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 19:577–583

    PubMed  CAS  Google Scholar 

  96. Osella-Abate S, Quaglino P, Savoia P, Leporati C, Comessatti A, Bernengo MG (2002) VEGF-165 serum levels and tyrosinase expression in melanoma patients: correlation with the clinical course. Melanoma Res 12:325–334

    PubMed  CAS  Google Scholar 

  97. Shih CH, Ozawa S, Ando N, Ueda M, Kitajima M (2000) Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res 6:1161–1168

    PubMed  CAS  Google Scholar 

  98. Kato H, Yoshikawa M, Miyazaki T, Nakajima M, Fukai Y, Masuda N, Fukuchi M, Manda R, Tsukada K, Kuwano H (2002) Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) in esophageal squamous cell carcinoma. Anticancer Res 22:3977–3984

    PubMed  CAS  Google Scholar 

  99. Ahn MJ, Jang SJ, Park YW, Choi JH, Oh HS, Lee CB, Paik HK, Park CK (2002) Clinical prognostic values of vascular endothelial growth factor, microvessel density, and p53 expression in esophageal carcinomas. J Korean Med Sci 17:201–207

    PubMed  CAS  Google Scholar 

  100. Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB, Carson LF, Ramakrishnan S (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80:98–106

    PubMed  CAS  Google Scholar 

  101. Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T (1997) Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer 76:1221–1227

    PubMed  CAS  Google Scholar 

  102. Garzetti GG, Ciavattini A, Lucarini G, Pugnaloni A, De Nictolis M, Amati S, Romanini C, Biagini G (1999) Vascular endothelial growth factor expression as a prognostic index in serous ovarian cystoadenocarcinomas: relationship with MIB1 immunostaining. Gynecol Oncol 73:396–401

    PubMed  CAS  Google Scholar 

  103. Raspollini MR, Amunni G, Villanucci A, Baroni G, Boddi V, Taddei GL (2004) Prognostic significance of microvessel density and vascular endothelial growth factor expression in advanced ovarian serous carcinoma. Int J Gynecol Cancer 14:815–823

    PubMed  CAS  Google Scholar 

  104. Ikeda N, Adachi M, Taki T, Huang C, Hashida H, Takabayashi A, Sho M, Nakajima Y, Kanehiro H, Hisanaga M, Nakano H, Miyake M (1999) Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 79:1553–1563

    PubMed  CAS  Google Scholar 

  105. Borre M, Nerstrom B, Overgaard J (2000) Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res 6:1882–1890

    PubMed  CAS  Google Scholar 

  106. George DJ, Halabi S, Shepard TF, Vogelzang NJ, Hayes DF, Small EJ, Kantoff PW (2001) Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 7:1932–1936

    PubMed  CAS  Google Scholar 

  107. Obermair A, Kohlberger P, Bancher-Todesca D, Tempfer C, Sliutz G, Leodolter S, Reinthaller A, Kainz C, Breitenecker G, Gitsch G (1996) Influence of microvessel density and vascular permeability factor/vascular endothelial growth factor expression on prognosis in vulvar cancer. Gynecol Oncol 63:204–209

    PubMed  CAS  Google Scholar 

  108. Gasparini G (2000) Prognostic value of vascular endothelial growth factor (VEGF) in breast cancer. Oncologist 5(Suppl 1):37–44

    PubMed  CAS  Google Scholar 

  109. Nakasaki T, Wada H, Shigemori C, Miki C, Gabazza EC, Nobori T, Nakamura S, Shiku H (2002) Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer. Am J Hematol 69:247–254

    PubMed  CAS  Google Scholar 

  110. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55:3964–3968

    PubMed  CAS  Google Scholar 

  111. Giatromanolaki A, Koukourakis MI, Kakolyris S, Turley H, O’Byrne K, Scott PA, Pezzella F, Georgoulias V, Harris AL, Gatter KC (1998) Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. Clin Cancer Res 4(12):3017–3024

    PubMed  CAS  Google Scholar 

  112. Meunier-Carpentier S, Dales JP, Djemli A, Garcia S, Bonnier P, Andrac-Meyer L, Lavaut MN, Allasia C, Charpin C (2005) Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma. Int J Oncol 26(4):977–984

    PubMed  CAS  Google Scholar 

  113. Seto T, Higashiyama M, Funai H, Imamura F, Uematsu K, Seki N, Eguchi K, Yamanaka T, Ichinose Y (2006) Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer. Lung Cancer 53(1):91–96

    PubMed  Google Scholar 

  114. Chung GG, Yoon HH, Zerkowski MP, Ghosh S, Thomas L, Harigopal M, Charette LA, Salem RR, Camp RL, Rimm DL, Burtness BA. (2006) Vascular endothelial growth factor, FLT-1, and FLK-1 analysis in a pancreatic cancer tissue microarray. Cancer 106(8):1677–1684

    PubMed  CAS  Google Scholar 

  115. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599

    PubMed  CAS  Google Scholar 

  116. Margolin K, Gordon MS, Holmgren E, Gaudreault J, Novotny W, Fyfe G, Adelman D, Stalter S, Breed J (2001) Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 19:851–856

    PubMed  CAS  Google Scholar 

  117. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843–850

    PubMed  CAS  Google Scholar 

  118. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    PubMed  CAS  Google Scholar 

  119. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    PubMed  CAS  Google Scholar 

  120. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65

    PubMed  CAS  Google Scholar 

  121. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Randolph HJ, Mass R, Perrou B, Nelson B, Novotny WF (2005) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23:3697–3705

    PubMed  CAS  Google Scholar 

  122. Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, Johnson DH (2005) Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an eastern cooperative oncology group (ECOG) trial—E4599. In: Proceedings of the American Society of Clinical Oncology (abstract LBA4)

  123. Miller K (2005) First-line bevacizumab and paclitaxel in patients with locally recurrent or metastatic breast cancer: a randomized, phase III trial coordinated by the Eastern Cooperative Oncology Group (E2100) (Abstract 3). Breast Cancer Res Treat 94:S6

    Google Scholar 

  124. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434

    PubMed  CAS  Google Scholar 

  125. Hillan KJ, Koeppen HKW, Tobin P, Pham T, Landon TH, Miller KD, Holmes FA, Cobleigh MA, Reimann JD, Langmuir VK (2003) The role of VEGF expression in response to bevacizumab plus capecitabine in metastatic breast cancer (MBC). In: Proceedings of the American Society of Clinical Oncology (abstract 766)

  126. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799

    PubMed  CAS  Google Scholar 

  127. Holden SN, Ryan E, Kearns A, Holmgren E, Hurwitz H (2005) Benefit from bevacizumab (BV) is independent of pretreatment plasma vascular endothelial growth factor-A (pl-VEGF) in patients (pts) with metastatic colorectal cancer (mCRC). In: Proceedings of the American Society of Clinical Oncology (abstract 3555)

  128. Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, Kabbinavar F, Holden SN, Novotny WF, Frantz GD, Hillan KJ, Koeppen H (2006) Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24:217–227

    PubMed  CAS  Google Scholar 

  129. Reese DM, Fratesi P, Corry M, Novotny W, Holmgren E, Small EJ (2001) A phase II trial of humanized anti-vascular endothelial growth factor antibody for the treatment of androgen-independent prostate cancer. Prostate J 3:65–70

    Google Scholar 

  130. Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM (1996) Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 93:10589–10594

    PubMed  CAS  Google Scholar 

  131. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA (1996) Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 93:10595–10599

    PubMed  CAS  Google Scholar 

  132. Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP (1997) The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. 17(9):5629–5639

    PubMed  CAS  Google Scholar 

  133. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, Vokes EE (2006) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23(31):8033–8040

    Google Scholar 

  134. O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM (2003a) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605

    CAS  Google Scholar 

  135. Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang X, Chen H, Sistla A, Luu TC, Tang F, Wei J, Tang C (2003) Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46:1116–1119

    PubMed  CAS  Google Scholar 

  136. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    PubMed  CAS  Google Scholar 

  137. Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O’Reilly T, Persohn E, Rosel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60:2178–2189

    PubMed  CAS  Google Scholar 

  138. Hennequin LF, Stokes ES, Thomas AP, Johnstone C, Ple PA, Ogilvie DJ, Dukes M, Wedge SR, Kendrew J, Curwen JO (2002) Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Med Chem 45:1300–1312

    PubMed  CAS  Google Scholar 

  139. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley AL, Hennequin LF (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655

    PubMed  CAS  Google Scholar 

  140. O’Farrell AM, Deprimo SE, Manning WC et al (2003). Analysis of biomarkers of SU11248 action in an exploratory study in patients with advanced malignancies. In: Proceedings of the American Society of Clinical Oncology (abstract 939)

  141. Raymond E, Faivre S, Vera K, Delbaldo C, Robert C, Spatz A, Bello C, Brega N, Scigalla P, Armand JP, Group ftSW (2003) Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. In: Proceedings of the American Society of Clinical Oncology (abstract 769)

  142. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24

    PubMed  CAS  Google Scholar 

  143. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25–35

    PubMed  CAS  Google Scholar 

  144. George D, Michaelson D, Oh WK, Reitsma D, Laurent D, Mietlowski W, Wang Y, Dugan M, Kaelin WG, Kantoff P (2003) Phase I study of PTK787/ZK 222584 (PTK/ZK) in metastatic renal cell carcinoma. In: Proceedings of the American Society of Clinical Oncology (abstract 1548)

  145. Roboz GJ, Giles FJ, List AF, Apostolidou E, Rae PE, Dugan M, Oasman SJ, Schuster MW, Laurent D, Feldman EJ (2003) Phase I trial PTK787/ZK 222584 (PTK/ZK), an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). In: Proceedings of the American Society of Clinical Oncology (abstract 2284)

  146. Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, Mross K, Medinger M, Lee L, Pinheiro J, Wood J, Thomas AL, Unger C, Henry A, Steward WP, Laurent D, Lebwohl D, Dugan M, Marme D (2005) Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Ann Oncol 16:558–565

    PubMed  CAS  Google Scholar 

  147. Conrad C, Friedman H, Reardon D, Provenzale J, Jackson E, Serjuddin H, Laurent D, Chen B (2004) A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). In: Proceedings of the American Society of Clinical Oncology (abstract 1512)

  148. Reardon D, Friedman H, Yung WKA, Brada M, Conrad C, Provenzale J, Jackson E, Serajuddin H, Chen B, Laurent D (2004) A phase I/II trial of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme (GBM). In: Proceedings of the American Society of Clinical Oncology (abstract 1513)

  149. Steward WP, Thomas A, Morgan B, Wiedenmann B, Bartel C, Vanhoefer U, Trarbach T, Junker U, Laurent D, Lebwohl D (2004) Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer. In: Proceedings of the American Society of Clinical Oncology (abstract 3556)

  150. Schleucher N, Trarbach T, Junker U, Tewes M, Masson E, Lebwohl D, Seeber S, Laurent D, Vanhoefer U (2004) Phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer. In: Proceedings of the American Society of Clinical Oncology (abstract 3558)

  151. Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, Masson E, Laurent D, Steward WP (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23(18):4162–4171

    PubMed  CAS  Google Scholar 

  152. Trarbach T, Schleucher N, Junker U, Tewes M, Masson E, Lebwohl D, Seeber S, Laurent D, Vanhoefer U, Steward W (2005) Phase I/II study of PTK/ZK, a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer. Eur J Cancer 3(Suppl):180 (abstract 639)

    Google Scholar 

  153. Mross K, Drevs J, Muller M, Medinger M, Marme D, Hennig J, Morgan B, Lebwohl D, Masson E, Ho YY, Gunther C, Laurent D, Unger C (2005) Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41:1291–1299

    PubMed  CAS  Google Scholar 

  154. Hecht JR, Trarbach T, Jaeger E, Hainsworth J, Wolff R, Lloyd K, Bodoky G, Borner M, Laurent D, Jacques C (2005) A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1). In: Proceedings of the American Society of Clinical Oncology (abstract LBA3)

  155. Dev IK, Dornsife RE, Hopper TM, Onori JA, Miller CG, Harrington LE, Dold KM, Mullin RJ, Johnson JH, Crosby RM, Truesdale AT, Epperly AH, Hinkle KW, Cheung M, Stafford JA, Luttrell DK, Kumar R (2004) Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models. Br J Cancer 91:1391–1398

    PubMed  CAS  Google Scholar 

  156. Inoue K, Slaton JW, Davis DW, Hicklin DJ, McConkey DJ, Karashima T, Radinsky R, Dinney CP (2000) Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res 6:2635–2643

    PubMed  CAS  Google Scholar 

  157. Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK, Suit HD (2001) Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 61:39–44

    PubMed  CAS  Google Scholar 

  158. Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB (2002) Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol 161:1917–1924

    PubMed  CAS  Google Scholar 

  159. Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65:671–680

    PubMed  CAS  Google Scholar 

  160. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB (2005) High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the eastern cooperative oncology group (ECOG) study E3200. In: Proceedings of the American Society of Clinical Oncology (abstract 2)

  161. Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268

    PubMed  CAS  Google Scholar 

  162. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    PubMed  CAS  Google Scholar 

  163. Minagawa N, Nakayama Y, Hirata K, Onitsuka K, Inoue Y, Nagata N, Itoh H (2002) Correlation of plasma level and immunohistochemical expression of vascular endothelial growth factor in patients with advanced colorectal cancer. Anticancer Res 22:2957–2963

    PubMed  CAS  Google Scholar 

  164. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    PubMed  CAS  Google Scholar 

  165. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101–111

    PubMed  CAS  Google Scholar 

  166. Beaudry P, Force J, Naumov GN, Wang A, Baker CH, Ryan A, Soker S, Johnson BE, Folkman J, Heymach JV (2005) Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res 11:3514–3522

    PubMed  CAS  Google Scholar 

  167. Shaked Y, Ciarocchi A, Franco M, Lee CR, Man S, Cheung AM et al (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumours. Science 313:1785–1787

    PubMed  CAS  Google Scholar 

  168. Baker LH, Demetri GD, Mendelson DS, Rowinsky EK, McKeegan EM, Knight RA, Carlson DM, Lobell M (2005) A randomized phase 2 study of the thrombospondin-mimetic peptide ABT-510 in patients with advanced soft tissue sarcoma (STS). In: Proceedings of the American Society of Clinical Oncology (abstract 9013)

  169. Rugo H, Dickler M, Scott J, et al (2006). A Phase II trial of letrozole in combination with bevacizumab in patients with hormone receptor-positive metastatic breast cancer: correlation of response with circulating endothelial (CEC) and epithelial (CTC) cells. Eur J Cancer 4(Suppl):163 (abstract 395)

    Google Scholar 

  170. Willet CG, Boucher Y, Duda DG, di Tommaso E, Munn LL, Tong RT et al (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 34:8136–8138

    Google Scholar 

  171. Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G et al (2006) Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108(2):452–459

    PubMed  CAS  Google Scholar 

  172. Beerepoot LV, Radema SA, Witteveen EO, Thomas T, Wheeler C, Kempin S, Voest EE (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24(10):1491–1498

    PubMed  CAS  Google Scholar 

  173. Norden-Zfoni A, Manola J, Desai J, Morgan J, Bello CL, Deprimo SE, et al. (2005) Levels of circulating endothelial cells (CECs) and monocytes as pharmacodynamic markers of SU11248 activity in patients (pts) with metastatic imatinib-resistant GIST. J Clin Oncol 23 (Abstr 9036)

  174. Rugo HS, Dickler MN, Scott JH, Moore DH, Melisko M, Yeh BN et al (2005) Change in circulating endothelial cells (CEC) and tumor cells (CTC) in patients (pts) receiving bevacizumab and erlotinib for metastatic breast cancer (MBC) predicts stable disease at first evaluation. J Clin Oncol 23 (Abstr 525)

  175. Bertolini F, Shaked Y, Mancuso P, Kerbel RS (2006) The multifaceted circulating endothelial cells in cancer: towards marker and target identification. Nat Rev Cancer 6(11):835–845

    PubMed  CAS  Google Scholar 

  176. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D et al (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769–777

    PubMed  CAS  Google Scholar 

  177. Rehman S, Jayson GC (2005) Molecular imaging of antiangiogenic agents. Oncologist 10:92–103

    PubMed  CAS  Google Scholar 

  178. Miller JC, Pien HH, Sahani D, Sorensen AG (2005) Imaging angiogenesis: applications and potential drug development. J Natl Cancer Inst 97:172–187

    Article  PubMed  CAS  Google Scholar 

  179. Morgan B, Thomas AL, Drevs J, Hennig J, Buchert M, Jivan A et al (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK 787/ZD 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 21:3955–3964

    PubMed  CAS  Google Scholar 

  180. Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Chaan NG et al (2005) Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 23:5464–5473

    PubMed  CAS  Google Scholar 

  181. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    PubMed  CAS  Google Scholar 

  182. Davidoff AM, Ng CY, Zhang Y et al (2005) Careful decoy receptor titering is required to inhibit tumor angiogenesis while avoiding adversely altering VEGF bioavailability. Mol Ther 11:300–310

    PubMed  CAS  Google Scholar 

  183. Uthoff SM, Duchrow M, Schmidt MH et al (2002) VEGF isoforms and mutations in human colorectal cancer. Int J Cancer 101:32–36

    PubMed  CAS  Google Scholar 

  184. Kaio E, Tanaka S, Kitadai Y et al (2003) Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma. Oncology 64:61–73

    PubMed  CAS  Google Scholar 

  185. Agui T, McConkey DJ, Tanigawa N (2002) Comparative study of various biological parameters, including expression of survivin, between primary and metastatic human colonic adenocarcinomas. Anticancer Res 22:1769–1776

    PubMed  CAS  Google Scholar 

  186. Berney CR, Yang JL, Fisher RJ et al (1998) Vascular endothelial growth factor expression is reduced in liver metastasis from colorectla cancer and correlates with urokinase-type plasminogen activator. Anticancer Res 18:973–977

    PubMed  CAS  Google Scholar 

  187. Jubb AM, Oates AJ, Holden S, Koeppen H (2006) Predicting benefit from anti-angiogenic agents in malignancy. Nat Med 6:626–635

    CAS  Google Scholar 

  188. Gutman S, Kessler LG (2006) The US Food and Drug Administration perspective on cancer biomarker development. Nat Rev Cancer 6:565–571

    PubMed  CAS  Google Scholar 

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Longo, R., Gasparini, G. Challenges for patient selection with VEGF inhibitors. Cancer Chemother Pharmacol 60, 151–170 (2007). https://doi.org/10.1007/s00280-006-0403-6

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