, Volume 14, Issue 4, pp 216–225 | Cite as

Antiangiogéniques: les anciens et les nouveaux

Mise au Point / Update


L’angiogenèse constitue un processusmajeur de la progression tumorale, en particulier en favorisant la croissance des cellules malignes et leur dissémination sous forme de métastases. Depuis une dizaine d’années, le développement de thérapies ciblées antiangiogéniques connaît un grand engouement. Depuis la découverte du bevacizumab, de nombreuses autres thérapies ont été développées. Parmi elles, les inhibiteurs de l’activité tyrosinekinase des récepteurs proangiogéniques comme le VEGFR sont aujourd’hui les plus étudiés. La recherche actuelle est basée sur le développement de nouvelles thérapies ciblées pouvant inhiber l’activité de plusieurs récepteurs avec une grande affinité. Cette revue reprend les données actuelles sur les thérapies ciblées antiangiogéniques disponibles et en cours de développement.

Mots clés

Angiogenèse VEGF Thérapies ciblées Inhibiteurs de tyrosine-kinase 

Angiogenesis: old and new agents


Angiogenesis constitutes a major process in cancer progression, especially by promoting the growth of malignant cells and dissemination of metastases. The development of anti-angiogenic targeted therapies has made significant progress over the last decade. Since the discovery of bevacizumab, numerous therapies have been designed. Among them, small molecules that inhibit the tyrosine-kinase activity of pro-angiogenic receptors such as VEGFR, are the most studied today. Current research focuses on the development of new targeted-therapies, able to inhibit the activity of several receptors at the same time and with a greater affinity. This article reviews the data on anti-angiogenic targetedtherapies, from available molecules to drugs still in the process of development.


Angiogenesis VEGF Targeted-therapies Tyrosinekinase inhibitors 


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  1. 1.
    Allegra CJ, Yothers G, O’Connell MJ, et al. (2011) Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 29(1): 11–16PubMedCrossRefGoogle Scholar
  2. 2.
    Anargyrou K, Dimopoulos MA, Sezer O, Terpos E (2008) Novel anti-myeloma agents and angiogenesis. Leuk Lymphoma 49(4): 677–689PubMedCrossRefGoogle Scholar
  3. 3.
    Ansari J, Glaholm J, McMenemin R, et al. (2010) Recent advances and future directions in the management of metastatic renal cell carcinoma. Anticancer Agents Med Chem 10(3): 225–235PubMedGoogle Scholar
  4. 4.
    Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin Cancer Biol 19(5): 329–337PubMedCrossRefGoogle Scholar
  5. 5.
    Cabebe E, Wakelee H (2006) Sunitinib: a newly approved small-molecule inhibitor of angiogenesis. Drugs Today (Barc) 42(6): 387–398CrossRefGoogle Scholar
  6. 6.
    Calvani N, Morelli F, Leo S, et al. (2011) Sequential use of sorafenib and sunitinib in advanced renal cell carcinoma: does the order of sequencing matter? Med Oncol [Epub ahead of print]Google Scholar
  7. 7.
    Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6(8): 465–477PubMedCrossRefGoogle Scholar
  8. 8.
    Chu E (2012) An update on the current and emerging targeted agents in meta-static colorectal cancer. Clin Colorectal Cancer 11(1): 1–13PubMedCrossRefGoogle Scholar
  9. 9.
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91(9): 4082–4085PubMedCrossRefGoogle Scholar
  10. 10.
    De Luca A, Normanno N (2010) Tivozanib, a pan-VEGFR tyrosine-kinase inhibitor for the potential treatment of solid tumors. IDrugs 13(9): 636–645PubMedGoogle Scholar
  11. 11.
    Deshpande HA, Gettinger S, Sosa JA (2010) Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer. Core Evid 4: 43–48PubMedGoogle Scholar
  12. 12.
    Dowlati A (2010) Hunting and trapping the vascular endothelial growth factor. J Clin Oncol 28(2): 185–187PubMedCrossRefGoogle Scholar
  13. 13.
    Eskens FA, de Jonge MJ, Bhargava P, et al. (2011) Biological and clinical activity of tivozanib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine-kinases, in a 4 week on, 2 week off schedule in patients with advanced solid tumors. Clin Cancer Res 17(22): 7156–7163PubMedCrossRefGoogle Scholar
  14. 14.
    Figueiras RG, Padhani AR, Goh VJ, et al. (2011) Novel oncologic drugs: what they do and how they affect images. Radiographics 31(7): 2059–2091PubMedCrossRefGoogle Scholar
  15. 15.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21): 1182–1186PubMedCrossRefGoogle Scholar
  16. 16.
    Folkman J (1974) Tumor angiogenesis. Adv Cancer Res 19(0): 331–358PubMedCrossRefGoogle Scholar
  17. 17.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16): 15–18PubMedGoogle Scholar
  18. 18.
    Fruehauf JP, Lutzky J, McDermott DF, et al. (2011) Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, 3, in patients with metastatic melanoma. Clin Cancer Res 17(23): 7462–7469PubMedCrossRefGoogle Scholar
  19. 19.
    Garcia JA, Roberts LR (2012) Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. J Hepatol 56(2): 486–487PubMedCrossRefGoogle Scholar
  20. 20.
    Gasparini G (2001) Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2(12): 733–740PubMedCrossRefGoogle Scholar
  21. 21.
    Gild ML, Bullock M, Robinson BG, Clifton-Bligh R (2011) Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 7(10): 617–624PubMedCrossRefGoogle Scholar
  22. 22.
    Glen H, Mason S, Patel H, et al. (2011) E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer 11: 309PubMedCrossRefGoogle Scholar
  23. 23.
    Grünwald V, Seidel C, Fenner M, et al. (2011) Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies. Br J Cancer 105: 1635–1639PubMedCrossRefGoogle Scholar
  24. 24.
    Hahn O, Stadler W (2006) Sorafenib. Curr Opin Oncol 18(6): 615–621PubMedCrossRefGoogle Scholar
  25. 25.
    Heldin CH, Westermark B (1990) Signal transduction by the receptors for platelet-derived growth factor. J Cell Sci 96(Pt 2): 193–196PubMedGoogle Scholar
  26. 26.
    Herbst RS, Hong D, Chap L, et al. (2009) Safety, pharmacokinetics, and antitumor activity of AMG-386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol 27(21): 3557–3565PubMedCrossRefGoogle Scholar
  27. 27.
    Ho TH, Jonasch E (2011) Axitinib in the treatment of metastatic renal cell carcinoma. Future Oncol 7(11): 1247–1253PubMedCrossRefGoogle Scholar
  28. 28.
    Hwang C, Heath EI (2010) Angiogenesis inhibitors in the treatment of prostate cancer. J Hematol Oncol 3: 26PubMedCrossRefGoogle Scholar
  29. 29.
    Ishikawa T, Kanda T, Kosugi S, et al. (2011) Sunitinib as a second-line therapy for imatinib-resistant gastrointestinal stromal tumors. Gan To Kagaku Ryoho 38(6): 916–921PubMedGoogle Scholar
  30. 30.
    Khoury CC, Ziyadeh FN (2011) Angiogenic factors. Contrib Nephrol 170: 83–92. Epub 2011 Jun 9PubMedCrossRefGoogle Scholar
  31. 31.
    Ledermann JA, Hackshaw A, Kaye S, et al. (2011) Randomized phase II placebocontrolled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 29(28): 3798–3804PubMedCrossRefGoogle Scholar
  32. 32.
    Leighl NB, Raez LE, Besse B, et al. (2010) A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac Oncol 5(7): 1054–1059PubMedGoogle Scholar
  33. 33.
    Lindsay CR, MacPherson IR, Cassidy J (2009) Current status of cediranib: the rapid development of a novel antiangiogenic therapy. Future Oncol 5(4): 421–432PubMedCrossRefGoogle Scholar
  34. 34.
    Melichar B, Studentová H, Zezulová M (2011) Pazopanib: a new multiple tyrosine kinase inhibitor in the therapy of metastatic renal cell carcinoma and other solid tumors. J BUON 16(2): 203–209PubMedGoogle Scholar
  35. 35.
    Merino M, Pinto A, González R, Espinosa E (2011) Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer. Eur J Cancer 47(12): 1846–1851PubMedCrossRefGoogle Scholar
  36. 36.
    Miller MT, Strömland K (1999) Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology 60(5): 306–321PubMedCrossRefGoogle Scholar
  37. 37.
    Monk BJ, Willmott LJ, Sumner DA (2010) Anti-angiogenesis agents in metastatic or recurrent cervical cancer. Gynecol Oncol 116(2): 181–186PubMedCrossRefGoogle Scholar
  38. 38.
    Moserle L, Amadori A, Indraccolo S (2009) The angiogenic switch: implications in the regulation of tumor dormancy. Curr Mol Med 9(8): 935–941PubMedCrossRefGoogle Scholar
  39. 39.
    Motzer RJ, Bukowski RM (2006) Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 24(35): 5601–5608PubMedCrossRefGoogle Scholar
  40. 40.
    Oberstein PE, Saif MW (2011) Novel agents in the treatment of unresectable neuroendocrine tumors. Highlights from the “2011 ASCO Annual Meeting”. Chicago, IL, USA; June 3–7, 2011. JOP 12(4): 358–361PubMedGoogle Scholar
  41. 41.
    Qi WX, Tang LN, He AN, et al. (2011) The role of vandetanib in the second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of four randomized controlled trials. Lung 189(6): 437–443PubMedCrossRefGoogle Scholar
  42. 42.
    Ranieri G, Patruno R, Ruggieri E, et al. (2006) Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 13(16): 1845–1857PubMedCrossRefGoogle Scholar
  43. 43.
    Razumilava N, Gores GJ (2011) Sorafenib for HCC: a pragmatic perspective. Oncology (Williston Park) 25(3): 300, 302Google Scholar
  44. 44.
    Reinhold HS, van den Berg-Blok A (1984) Factors influencing the neovascularization of experimental tumours. Biorheology 21(4): 493–501PubMedGoogle Scholar
  45. 45.
    Richardson PG, Hideshima T, Anderson KC (2003) Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control 10(5): 361–369PubMedGoogle Scholar
  46. 46.
    Rini BI, Escudier B, Tomczak P, et al. (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378(9807): 1931–1939PubMedCrossRefGoogle Scholar
  47. 47.
    Risau W (1998) Angiogenesis is coming of age. Circ Res 82(8): 926–928PubMedGoogle Scholar
  48. 48.
    Risau W (1998) Development and differentiation of endothelium. Kidney Int Suppl 67: S3–S6PubMedCrossRefGoogle Scholar
  49. 49.
    Robson EJ, Ghatage P (2011) AMG-386: profile of a novel angiopoietin antagonist in patients with ovarian cancer. Expert Opin Investig Drugs 20(2): 297–304PubMedCrossRefGoogle Scholar
  50. 50.
    Shahshahan MA, Beckley MN, Jazirehi AR (2011) Potential usage of proteasome inhibitor bortezomib (Velcade, PS-341) in the treatment of metastatic melanoma: basic and clinical aspects. Am J Cancer Res 1(7): 913–924PubMedGoogle Scholar
  51. 51.
    Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28(11): 1779–1802PubMedCrossRefGoogle Scholar
  52. 52.
    Sloan B, Scheinfeld NS (2008) Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs 9(12): 1324–1335PubMedGoogle Scholar
  53. 53.
    Sobrero AF, Bruzzi P (2011) Vatalanib in advanced colorectal cancer: two studies with identical results. J Clin Oncol 29(15): 1938–1940PubMedCrossRefGoogle Scholar
  54. 54.
    Spratlin JL, Cohen RB, Eadens M, et al. (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28(5): 780–787PubMedCrossRefGoogle Scholar
  55. 55.
    Spratlin JL, Mulder KE, Mackey JR (2010) Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Future Oncol 6(7): 1085–1094PubMedCrossRefGoogle Scholar
  56. 56.
    Stewart MW (2011) Aflibercept (VEGFTRAP): the next anti-VEGF drug. Inflamm Allergy Drug Targets 10(6): 497–508PubMedGoogle Scholar
  57. 57.
    Stoelting S, Trefzer T, Kisro J, et al. (2008) Low-dose oral metronomic chemotherapy prevents mobilization of endothelial progenitor cells into the blood of cancer patients. In Vivo 22(6): 831–836PubMedGoogle Scholar
  58. 58.
    Tageja N (2011) Lenalidomide: current understanding of mechanistic properties. Anticancer Agents Med Chem 11(3): 315–326PubMedGoogle Scholar
  59. 59.
    Takami HE (2011) Current status of molecularly targeted drugs for the treatment of advanced thyroid cancer. Endocr J 58(3): 151–153PubMedCrossRefGoogle Scholar
  60. 60.
    Uraizee I, Cheng S, Moslehi J (2011) Reversible cardiomyopathy associated with sunitinib and sorafenib. N Engl J Med 365(17): 1649–1650PubMedCrossRefGoogle Scholar
  61. 61.
    Voorhees PM, Dees EC, O’Neil B, Orlowski RZ (2003) The proteasome as a target for cancer therapy. Clin Cancer Res 9(17): 6316–6325PubMedGoogle Scholar
  62. 62.
    Wilhelm SM, Dumas J, Adnane L, et al. (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129(1): 245–255PubMedCrossRefGoogle Scholar
  63. 63.
    Zustovich F, Lombardi G, Nicoletto O, Pastorelli D (2011) Second-line therapy for refractory renal-cell carcinoma. Crit Rev Oncol Hematol [Epub ahead of print]Google Scholar

Référence électronique

  1. 64.

Copyright information

© Springer Verlag France 2012

Authors and Affiliations

  1. 1.Service d’oncologie médicalehôpital Pitié-SalpétrièreParisFrance

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