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Circulating Vascular Endothelial Growth Factor

Methods, Prognostic Significance, and Potential Application for Antiangiogenic Therapy
  • Roberta Sarmiento
  • Roberta Franceschini
  • Sabrina Meo
  • Massimo Gion
  • Raffele Longo
  • Giampietro Gasparini
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Despite significant advances in early detection and treatment, breast cancer still remains the major cause of cancer-related death in women. Many studies suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is the complex process leading to the formation of new blood vessels from pre-existing vascular network. The VEGF is the most active growth factor involved in angiogenesis; more specifically, raised intratumoral VEGF concentrations have been shown to correlate with tumor aggressiveness. VEGF is therefore a promising target for new therapies, but it is still unclear in which blood matrix the determination of VEGF is more accurate as a cancer biomarker and which matrix provides the optimal clinical information. Circulating levels of VEGF have been measured by several investigators who reported conflicting results. However, these studies are not comparable with each other due to a lack of standardization of the pre-analytical phase. The chapter presents the main studies concerning anti-VEGF therapies; several studies evaluated the safety profile and activity of the combination of standard chemotherapy with new antiangiogenic agents. However, to date only a few definitive results on the effect of angiogenesis blood markers have been reported. Determination of circulating VEGF still remains an experimental procedure with no evident application for routine clinical decisions. Data from retrospective studies, however, suggest that VEGF levels may predict clinical outcome of breast cancer.

Key Words

Vascular endothelial growth factor breast cancer angiogenesis therapy prognosis 

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References

  1. 1.
    Rosen LE. Clinical experience with angiogenesis signalling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 2002;19:36–44.Google Scholar
  2. 2.
    Gasparini G. Clinical significance of determination of surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol 2001;37:97–114.Google Scholar
  3. 3.
    Linchtenbeld HC, Barendsz-Janson AF, van Essen H, Struijker Boudier H, Griffioen AW, Hillen HF. Angiogenic potential of malignant and non-malignant human breast tissues in an in vivo angiogenesis model. Int J Cancer 1998;77:455–459.Google Scholar
  4. 4.
    McLeskey SW, Tobias CA, Vezza PR, Filie AC, Kern FG, Hanfelt J. Tumor growth of FGF or VEGF transfected angiogenic factor. Am J Pathol 1998;153:1993–2006.PubMedGoogle Scholar
  5. 5.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. NEngl J Med 1991;324:1–8.Google Scholar
  6. 6.
    Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early stage breast carcinoma. J Natl Cancer Inst 1992;84:1875–1887.PubMedGoogle Scholar
  7. 7.
    Heimann R, Ferguson D, Powers C, Recant WM, Weischelbaum RR, Hellman S. Angiogenesis as a predictor of long-term survival for patients with node negative breast cancer. J Natl Cancer Inst 1996;88:1764–1769.PubMedGoogle Scholar
  8. 8.
    Relf M, et al. Expression of the angiogenic factors vascular endothelial growth factor, acidic and basic fibroblast growth factor, tumour growth factor-b-1, platelet-derived endothelial cell growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–969.PubMedGoogle Scholar
  9. 9.
    Carmeliet P, et al. Role of HIF-1α hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998;394:485–490.PubMedGoogle Scholar
  10. 10.
    Fukumura D, et al. Tumour induction of VEGF promoter activity in stromal cells. Cell 1998;94:715–725.PubMedGoogle Scholar
  11. 11.
    Ferrara N, Bunting S. Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens 1996;5:35–44.PubMedGoogle Scholar
  12. 12.
    Ferrara N, Alitalo K. Clinical application of angiogenic growth factors and their inhibitors. Nat Med 1999;1:120–122.Google Scholar
  13. 13.
    Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989;246:1309–1312.PubMedGoogle Scholar
  14. 14.
    Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992;189:824–831.PubMedGoogle Scholar
  15. 15.
    Roberts WG, Palade GE. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 1997;57:765–772.PubMedGoogle Scholar
  16. 16.
    Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;77:186–191.Google Scholar
  17. 17.
    Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192–198.PubMedGoogle Scholar
  18. 18.
    Kliche S, Waltenberger J. VEGF receptor signaling and endothelial function. JUBMB Life 2001;52:61–66.Google Scholar
  19. 19.
    Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735–742.PubMedGoogle Scholar
  20. 20.
    Gluzman-Poltorak Z, Cohen T, Shibuya M, et al. Vascular endothelial growth factor receptor-1 (VEGFR-1) and neuropilin-2 form complexes. J Biol Chem 2001;276:18688–18694.PubMedGoogle Scholar
  21. 21.
    Fuh G, Garcia KC, DeVos AM. The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem 2000;275:26690–26695.PubMedGoogle Scholar
  22. 22.
    Dvorak HF, Brown LF, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability and angiogenesis. Am J Pathol 1995;146:1029–1039.PubMedGoogle Scholar
  23. 23.
    Ferrara N. VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol 2000;11:517–524.Google Scholar
  24. 24.
    Banerji S, et al. Lyve-1, a new homologue of the CD44 glycoprotein is a lymph-specific receptor for hyaluran. J Cell Biol 1999;144:789–801.PubMedGoogle Scholar
  25. 25.
    Kurebayashi J, Otsuki T, Kunisue H, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res 1999;90:977–981.PubMedGoogle Scholar
  26. 26.
    Makinen T, Jussila L, Veikkola T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 2001;7:199–205.PubMedGoogle Scholar
  27. 27.
    Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000;55:15–35.PubMedGoogle Scholar
  28. 28.
    Neufeld G, Cohen T, Gengrinovitz S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.PubMedGoogle Scholar
  29. 29.
    Byrne GJ, Bundred NJ. Surrogate markers of tumoral angiogenesis. Int J Biol Markers 2000;15:334–339.PubMedGoogle Scholar
  30. 30.
    Solorzano CC, Jung YD, Bucana CD, McConkey DJ, Gallick GE, McMahon G, Ellis LM. In vivo intracellular signaling as a marker of antiangiogenic activity. Cancer Res 2001;61:7048–7051.PubMedGoogle Scholar
  31. 31.
    Axelsson K, Ljung BM, Moore DH, et al. Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma. JNatl Cancer Inst 1996;87:997–1008.Google Scholar
  32. 32.
    Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997;89:139–147.PubMedGoogle Scholar
  33. 33.
    Toi M, Gion M, Biganzoli E, et al. Co-determination of the angiogenic factors thymidine phosphorylase and vascular endothelial growth factor in node-negative breast cancer: prognostic implications. Angiogenesis 1997;1:71–83.PubMedGoogle Scholar
  34. 34.
    Gasparini G, Toi M, Miceli R, et al. Clinical relevance of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in patients with node-positive breast cancer treated either with adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 1999;5:101–111.PubMedGoogle Scholar
  35. 35.
    Li C, Guo B, Bernabeu C, et al. Angiogenesis in breast cancer: the role of transforming growth factor beta and CD 105. Microsc Res Tech 2001;52:437–449.PubMedGoogle Scholar
  36. 36.
    Hormbrey E, et al. A critical review of VEGF analysis in peripheral blood: is the current literature meaningful? Clin Exp Metastas 2002;19:651–663.Google Scholar
  37. 37.
    Salgado R. Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study. Angiogenesis 2001;4:37–43.PubMedGoogle Scholar
  38. 38.
    Verheul HMW, Hoekman K, Luykx-de Bakker S, et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997;3:2187–2190.PubMedGoogle Scholar
  39. 39.
    Banks RE, Forbes MA, Kinsey SE, et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998;77:956–964.PubMedGoogle Scholar
  40. 40.
    Adams J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 2000;60:2898–2905.PubMedGoogle Scholar
  41. 41.
    Dittadi R, et al. Validation of blood collection procedures for the determination of circulating vascular endothelial growth factor (VEGF) in different blood compartments. Int J Biol Markers 2001;16:87–96.PubMedGoogle Scholar
  42. 42.
    Salven P, Mäenpää H, Orpana A, et al. Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin Cancer Res 1997;3:647–651.PubMedGoogle Scholar
  43. 43.
    Salven P, Orpana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res 1999;5:487–491.PubMedGoogle Scholar
  44. 44.
    Salven P, Perhoniemi V, Tykkä H, et al. Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res Treat 1999;53:161–166.PubMedGoogle Scholar
  45. 45.
    Benoy I, et al. Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. Clin Breast Cancer 2002;2:311–315.PubMedGoogle Scholar
  46. 46.
    Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–1225 (Review).PubMedGoogle Scholar
  47. 47.
    Heer K, Kumar H, Speirs V, et al. Vascular endothelial growth factor in premeno-pausal women-indicator of the best time for breast cancer surgery? Br J Cancer 1998;78:1203–1207.PubMedGoogle Scholar
  48. 48.
    Agraval R, Conway GS, Sladkevicius P, et al. Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow. Clin Endocrinol 1999;50:101–106.Google Scholar
  49. 49.
    Yamamoto Y, Toi M, Kondo S, et al. Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res 1996;2:821–826.PubMedGoogle Scholar
  50. 50.
    McILenny C, George WD, Doughty JC. A comparison of serum and plasma levels of vascular endothelial growth factor during the menstrual cycle in healthy volunteers. Br J Cancer 2002;86:1786–1789.Google Scholar
  51. 51.
    Meo S, Dittadi R, Gion M. Biological variation of circulating vascular endothelial growth factor (VEGF). Hamburger Symposium on Tumour Markers. December 3, 2003 (Abstr).Google Scholar
  52. 52.
    Hagedorn M, Bikfalvi A. Target molecules for anti-angiogenic therapy: frombasic research to clinical trials. Crit Rev Oncol Hematol 2000;34:89–110.PubMedGoogle Scholar
  53. 53.
    Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human antivascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843–850.PubMedGoogle Scholar
  54. 54.
    Sledge G, Miller K, Novotny W, et al. A Phase II trial of single-agent rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) in patients with relapsed metastatic breast cancer. ProcAm Soc Clin Oncol 19:3a, 2000 (Abstr 5c).Google Scholar
  55. 55.
    Miller KD, Rugo HS, Cbleigh MA, et al. Phase III trial of capecitabine (Xeloda) plus bevacizumab (Avastin) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with anthracycline and a taxane. Breast Cancer Res Treat 2002;76(Suppl)1:1 (Abstr 36).Google Scholar
  56. 56.
    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 1999;17:195–212.PubMedGoogle Scholar
  57. 57.
    Kozin S, Boucher Y, Hicklin D, et al. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 2001;61:39–44.PubMedGoogle Scholar
  58. 58.
    Smolich B, Yuen H, West K, et al. The angiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 2001;97:1413–1421.PubMedGoogle Scholar
  59. 59.
    Mendel D, Laird A, Smolich B, et al. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine activity, as an anti-angiogenesis agent. Anticancer Drug Des 2000;15:29–41.PubMedGoogle Scholar
  60. 60.
    Mendel D, Schreck R, West D, et al. The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res 2000;6:4848–4858.PubMedGoogle Scholar
  61. 61.
    Shaheen R, Tseng W, Davis D, et al. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res 2001;61:1454–1458.Google Scholar
  62. 62.
    Antonian L, Zhang H, Yang C, et al. Biotransformation of the anti-angiogenic compounds SU5416. Drug Metab Dispos 2000;28:1505–1512.PubMedGoogle Scholar
  63. 63.
    Drevs J, Hofmann I, Hugenschmidt H, et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factorreceptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 2000;60:4819–4824.PubMedGoogle Scholar
  64. 64.
    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;60:4152–4160.PubMedGoogle Scholar
  65. 65.
    Wood J, Bold G, Buchdunger E, et al. 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 2000;60:2178–2189.PubMedGoogle Scholar
  66. 66.
    Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumour vascularization, and growth of multiple tumour types. Cancer Res 1999;59:99–106.PubMedGoogle Scholar
  67. 67.
    Taylor ML, Metcalfe DD. Kit signal transduction. Hematol Oncol Clin North Am 2000;14:517–535.PubMedGoogle Scholar
  68. 68.
    Stopeck A, Sheldon M, Vahedian M, et al. Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 2002;8:2798–2805.PubMedGoogle Scholar
  69. 69.
    Minami H, Ebi H, Tahara M, et al. A Phase I study of an oral VEGF receptor tyrosine kinase inhibitor ZD6474, in Japanese patients with solid tumors. ProcAm Soc Clin Oncol 2003, Abstr 778.Google Scholar
  70. 70.
    Ruggeri B, Singh J, Gingrich D, et al. CEP-7055: a novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. Cancer Res 2003;63:5978–5991.PubMedGoogle Scholar
  71. 71.
    Hoekman K. SU6668, a multitargeted angiogenesis inhibitor. Cancer J 2001; (Suppl. 7)3:S134–138.Google Scholar
  72. 72.
    Thomas AL, et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584. Semin Oncol 2003;(Suppl. 6):32–38.Google Scholar
  73. 73.
    Toi M, Inada K, Suzuki H, Tominaga T. Tumour angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 1995;36:195–202.Google Scholar
  74. 74.
    Heer K, Kumar H, Read RJ, Fox JN, Monson JRT, Kerin MJ. Serum vascular endothelial growth factor in breast cancer: its relation with cancer type and estrogen receptor status. Clin Cancer Res 2001;7:3491–3494.PubMedGoogle Scholar
  75. 75.
    Kolch W, Martiny-Baron G, Kieser A, et al. Regulation of the expression of the VEGF/VPS and its receptors: role in tumour angiogenesis. Breast Cancer Res Treat 1995;36:139–155.PubMedGoogle Scholar
  76. 76.
    Shweiki D, Itin A, Neufeld G, et al. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Investig 1993;91:2235–2243.PubMedGoogle Scholar
  77. 77.
    Adama J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 2000;60:2898–2905.Google Scholar
  78. 78.
    Ferrer FA, Miller LJ, Andrawisi RI, et al. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol 1997;157:2329–2333.PubMedGoogle Scholar
  79. 79.
    Wu Y, Saldana L, Chillar R, Vadgama J, et al. Plasma vascular endothelial growth factor is useful in assessing progression of breast cancer post surgery and during adjuvant treatment. Int J Oncol 2002;20:509–516.PubMedGoogle Scholar
  80. 80.
    Nishimura R, Nagao K, Miyayama H, et al. Higher plasma vascular endothelial growth factor levels correlate with menopause, overexpression of p53, and recurrence of breast cancer. Breast Cancer 2003;10:120–128.PubMedGoogle Scholar
  81. 81.
    Zhao J, Yan F, Yu H, et al. Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer. Cancer Lett 2004;204:87–95.PubMedGoogle Scholar
  82. 82.
    Catalano G, Orditura M, Galizia G, et al. Increased vascular endothelial growth factor (VEGF) serum levels correlate with poor outcome in advanced colorectal cancer (CRC) patients. Proc Am Soc Clin Oncol Abstr 3522.Google Scholar
  83. 83.
    Lissoni P, Fumagalli E, Malugani F, et al. Chemotherapy and angiogenesis in advanced cancer: vascular endothelial growth factor (VEGF) decline as predictor of disease control during taxol therapy in metastatic breast cancer. Int J Biol Markers 2000;15:308–311.PubMedGoogle Scholar
  84. 84.
    Kindler HL, Ansari R, Lester E, et al. Bevacizumab (B) plus gemcitabine (G) in patients (pts) with advanced pancreatic cancer (PC). Proc Am Soc Clin Oncol 2003; Abstr 1037.Google Scholar
  85. 85.
    Carson WE, Biber J, Shah N, et al. A Phase 2 trial of a recombinant humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody in patients with malignant melanoma. Proc Am Soc Clin Oncol 2003 Abstr 2873.Google Scholar
  86. 86.
    Fanelli M, Sarmiento R, Gattuso D., et al. Thalidomide: a new anticancer drug? Expert Opin Invest Drugs 2003;12:1211–1225.Google Scholar
  87. 87.
    Baidas SM, Winer EP, Fleming GF, et al. Phase II evaluation of thalidomide in patients with metastatic breast cancer. J Clin Oncol 2000;18:2710–2717.PubMedGoogle Scholar
  88. 88.
    Nanus DM, Schmitz-Drager B J, Motzer RJ. Expression of basic fibroblast growth factor in primary human renal tumors: correlation with poor survival. JNatl Cancer Inst 1993;85:1597–1599.Google Scholar
  89. 89.
    Nathan PD, Eisen G. The biological treatment of renal cell carcinoma and melanoma. Lancet Oncol 2002;3:89–96.PubMedGoogle Scholar
  90. 90.
    Minor DR, Monroe D, D’Amico LA, et al. A Phase II study of thalidomide in advanced metastatic renal cell carcinoma. Invest New Drugs 2002;20:389–393.PubMedGoogle Scholar
  91. 91.
    O’Really MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277–285.Google Scholar
  92. 92.
    Bohem T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental therapy of experimental cancer does not induce acquired resistance. Nature 1997;390:404–407.Google Scholar
  93. 93.
    Herbst RS, Kenneth RH, Hai TT, et al. Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2002;20:3792–3803.PubMedGoogle Scholar
  94. 94.
    Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer 1997;76:238–243.PubMedGoogle Scholar
  95. 95.
    Benoy I, Vermeulen P, Wuyts H, et al. Vascular endothelial Cell Growth Factor (VEGF) serum concentrations change according to the phase of the menstrual cycle. EurJ Cancer 1998;34:1298–1299.Google Scholar
  96. 96.
    Maloney JP, Silliman CC, Ambruso DR, et al. In vitro release of vascular endothelial growth factor during platelet aggregation. Am J Physiol 1998;275 (Heart Circ Physiol 1998;44:H1054–H1061.Google Scholar
  97. 97.
    Webb NJA, Bottomley MJ, Watson CJ, et al. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci 1998;94:395–404.PubMedGoogle Scholar
  98. 98.
    Balsari A, Maier JAM, Colnaghi MI, et al. Correlation between tumor vascularity, vascular endothelial growth factor production by tumor cells, serum vascular endothelial growth factor levels, and serum angiogenic activity in patients with breast carcinoma. Lab Invest 1999;79:897–902.PubMedGoogle Scholar
  99. 99.
    Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 1999;85:178–187.PubMedGoogle Scholar
  100. 100.
    Wynendaele W, Derua R, Hoylaerts MF, et al. Vascular endothelial growth factor measured in platelet poor plasma allows optimal separation between cancer patients and volunteers: a key to study an angiogenic marker in vivo. Ann Oncol 1999;10:965–971.PubMedGoogle Scholar
  101. 101.
    Gunsilius E, Petzer A, Stockhammer G, et al. Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology 2000;58:169–174.PubMedGoogle Scholar
  102. 102.
    Lantzsch T, et al. The correlation between immunohistochemically-detected markers of angiogenesis and serum vascular endothelial growth factor in patients with breast cancer. Anticancer Res 2002;22:1925–1928.PubMedGoogle Scholar
  103. 103.
    Bachelot T, et al. 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 2003;88:1721–1726.PubMedGoogle Scholar
  104. 104.
    Caine GJ, Blann AD, Stonelake PS, Ryan P, Lip GYH. Plasma angiopoietin-1, angiopoietin-2, and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. EurJ Clin Invest 2003;33:883–890.Google Scholar
  105. 105.
    Bauer JA, Morrison B, Oates R, et al. Angyozime and interferon α2b synergistically inhibit tumor angiogenesis. ProcAmAssoc Cancer Res 2003;44 Abstr 1159.Google Scholar
  106. 106.
    Parry TJ, Bouhana KS, Blanchard KS, et al. Ribozyme pharmacokinetic screening for predicting pharmacodynamic dosing regimen. Curr Issues Mol Biol 2000;2:113–118.PubMedGoogle Scholar
  107. 107.
    Weng DE, Usman N. Angiozyme: a novel angiogenesis inhibitor. Curr Oncol Rep 2001;3:141–146.PubMedGoogle Scholar
  108. 108.
    Lee JK, Hong YJ, Han CJ, Hwang DY, Hong SI. Clinical usefulness of serum and plasma vascular endothelial growth factor in cancer patients: which is the optimal specimen? Int J Oncol 2000;17:149–152.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Roberta Sarmiento
    • 1
  • Roberta Franceschini
    • 2
  • Sabrina Meo
    • 2
  • Massimo Gion
    • 3
  • Raffele Longo
    • 1
  • Giampietro Gasparini
    • 1
  1. 1.Division of Medical OncologySan Filippo Neri HospitalRomeItaly
  2. 2.ABO Association c/o Centre for the Study of Biological Markers of MalignancyUnit of Laboratory Medicine, Regional General HospitalVeniceItaly
  3. 3.Centre for the Study of Biological Markers of Malignancy, Unit of Laboratory MedicineRegional General HospitalVeniceItaly

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