Current Hematologic Malignancy Reports

, Volume 3, Issue 1, pp 10–18

Antiangiogenic therapy in myelodysplastic syndromes: Is there a role?



Angiogenesis has been shown to play a pivotal role in the growth and metastasis of solid tumors. Numerous in vitro and translational research studies have implicated a role for angiogenesis in the pathogenesis of myelodysplastic syndrome (MDS). Although the role of angiogenesis inhibitors in the treatment of solid tumors has evolved significantly over the past 5 years, their role in the treatment of hematologic malignancies such as MDS remains investigational. MDS treatment historically has been challenging, but the US Food and Drug Administration in the past 4 years has approved the hypomethylating agents 5-azacitidine and decitabine and the immunomodulatory agent lenalidomide for the 5q-syndrome. These approvals highlight recent successes in identifying and targeting pathobiologic abnormalities that contribute to MDS. Drugs such as lenalidomide and the first-generation analogue from which it was derived, thalidomide, exert multiple mechanisms of action but partially act via inhibition of angiogenesis. Over the next 5 to 10 years, preclinical and clinical evaluation of agents with more strictly defined antiangiogenic activity, such as inhibitors of vascular endothelial growth factor, or agents with partial antiangiogenesis activity, such as multitargeted tyrosine kinase inhibitors, will ultimately help define the utility of angiogenic blockade in MDS.


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References and Recommended Reading

  1. 1.
    Carmeliet P: Angiogenesis in life, disease and medicine. Nature 2005, 438:932–936.PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–1186.PubMedCrossRefGoogle Scholar
  3. 3.
    Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342.PubMedCrossRefGoogle Scholar
  4. 4.
    Midgley R, Kerr D: Bevacizumab—current status and future directions. Ann Oncol 2005, 16:999–1004.PubMedCrossRefGoogle Scholar
  5. 5.
    Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125–134.PubMedCrossRefGoogle Scholar
  6. 6.
    Faivre S, Djelloul S, Raymond E: New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol 2006, 33:407–420.PubMedCrossRefGoogle Scholar
  7. 7.
    Rock EP, Goodman V, Jiang JX, et al.: Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007, 12:107–113.PubMedCrossRefGoogle Scholar
  8. 8.
    Brunner G, Nguyen H, Gabrilove J, et al.: Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood 1993, 81:631–638.PubMedGoogle Scholar
  9. 9.
    Leung DW, Cachianes G, Kuang WJ, et al.: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989, 246:1306–1309.PubMedCrossRefGoogle Scholar
  10. 10.
    Podar K, Anderson KC: The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005, 105:1383–1395.PubMedCrossRefGoogle Scholar
  11. 11.
    List AF: Vascular endothelial growth factor signaling pathway as an emerging target in hematologic malignancies. Oncologist 2001, 6(Suppl 5):24–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Ziegler BL, Valtieri M, Porada GA, et al.: KDR receptor: a key marker defining hematopoietic stem cells. Science 1999, 285:1553–1558.PubMedCrossRefGoogle Scholar
  13. 13.
    Aguayo A, Estey E, Kantarjian H, et al.: Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood 1999, 94:3717–3721.PubMedGoogle Scholar
  14. 14.
    Giles FJ: The vascular endothelial growth factor (VEGF) signaling pathway: a therapeutic target in patients with hematologic malignancies. Oncologist 2001, 6(Suppl 5):32–39.PubMedCrossRefGoogle Scholar
  15. 15.
    Hussong JW, Rodgers GM, Shami PJ: Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000, 95:309–313.PubMedGoogle Scholar
  16. 16.
    Aguayo A, Kantarjian H, Manshouri T, et al.: Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000, 96:2240–2245.PubMedGoogle Scholar
  17. 17.
    Lundberg LG, Lerner R, Sundelin P, et al.: Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol 2000, 157:15–19.PubMedGoogle Scholar
  18. 18.
    Vacca A, Ribatti D: Bone marrow angiogenesis in multiple myeloma. Leukemia 2006, 20:193–199.PubMedCrossRefGoogle Scholar
  19. 19.
    Rajkumar SV, Leong T, Roche PC, et al.: Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000, 6:3111–3116.PubMedGoogle Scholar
  20. 20.
    Kumar S, Gertz MA, Dispenzieri A, et al.: Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy. Bone Marrow Transplant 2004, 34:235–239.PubMedCrossRefGoogle Scholar
  21. 21.
    Pruneri G, Bertolini F, Soligo D, et al.: Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999, 81:1398–1401.PubMedCrossRefGoogle Scholar
  22. 22.
    Alexandrakis MG, Passam FH, Pappa CA, et al.: Serum evaluation of angiogenic cytokine basic fibroblast growth factor, hepatocyte growth factor and TNF-alpha in patients with myelodysplastic syndromes: correlation with bone marrow microvascular density. Int J Immunopathol Pharmacol 2005, 18:287–295.PubMedGoogle Scholar
  23. 23.
    Wimazal F, Krauth MT, Vales A, et al.: Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: correlation between VEGF expression and the FAB category. Leuk Lymphoma 2006, 47:451–460.PubMedCrossRefGoogle Scholar
  24. 24.
    Alexandrakis MG, Passam FH, Kyriakou DS, et al.: Expression of the proliferation-associated nuclear protein MIB-1 and its relationship with microvascular density in bone marrow biopsies of patients with myelodysplastic syndromes. J Mol Histol 2004, 35:857–863.PubMedCrossRefGoogle Scholar
  25. 25.
    Lundberg LG, Hellstrom-Lindberg E, Kanter-Lewensohn L, et al.: Angiogenesis in relation to clinical stage, apoptosis and prognostic score in myelodysplastic syndromes. Leuk Res 2006, 30:247–253.PubMedCrossRefGoogle Scholar
  26. 26.
    Keith T, Araki Y, Ohyagi M, et al.: Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. Br J Haematol 2007, 137:206–215.PubMedCrossRefGoogle Scholar
  27. 27.
    Aguayo A, Kantarjian HM, Estey EH, et al.: Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer 2002, 95:1923–1930.PubMedCrossRefGoogle Scholar
  28. 28.
    Bellamy WT, Richter L, Sirjani D, et al.: Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 2001, 97:1427–1434.PubMedCrossRefGoogle Scholar
  29. 29.
    Alexandrakis MG, Passam FH, Pappa CA, et al.: Relation between bone marrow angiogenesis and serum levels of angiogenin in patients with myelodysplastic syndromes. Leuk Res 2005, 29:41–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Brunner B, Gunsilius E, Schumacher P, et al.: Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia. J Hematother Stem Cell Res 2002, 11:119–125.PubMedCrossRefGoogle Scholar
  31. 31.
    Lai R, Estey E, Shen Y, et al.: Clinical significance of plasma endostatin in acute myeloid leukemia/myelodysplastic syndrome. Cancer 2002, 94:14–17.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu Q, Dey AL, Yang Y, et al.: Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes. Cancer 2004, 100:1884–1891.PubMedCrossRefGoogle Scholar
  33. 33.
    Alvi S, Borok RZ, Shaher A, et al.: Thalidomide significantly modifies bone marrow microenvironment in myelodysplastic syndrome (MDS) patients [abstract]. Blood 2002, 100:375a. Abstract 1454.CrossRefGoogle Scholar
  34. 34.
    Shetty V, Alvi S, Zorat F, et al.: Effect of the antiangiogenic thalidomide on the biological characteristics of patients with myelodysplastic syndromes [abstract]. Blood 2002, 100:337b. Abstract 4902.Google Scholar
  35. 35.
    Raza A, Meyer P, Dutt D, et al.: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001, 98:958–965.PubMedCrossRefGoogle Scholar
  36. 36.
    Moreno-Aspitia A, Colon-Otero G, Hoering A, et al.: Thalidomide therapy in adult patients with myelodysplastic syndrome. A North Central Cancer Treatment Group phase II trial. Cancer 2006, 107:767–772.PubMedCrossRefGoogle Scholar
  37. 37.
    Strupp C, Germing U, Aivado M, et al.: Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia 2002, 16:1–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Bouscary D, Legros L, Tulliez M, et al.: A non-randomised dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes: the Thal-SMD-2000 trial of the Groupe Francais des Myelodysplasies. Br J Haematol 2005, 131:609–618.PubMedCrossRefGoogle Scholar
  39. 39.
    Richardson PG, Schlossman RL, Weller E, et al.: Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002, 100:3063–3067.PubMedCrossRefGoogle Scholar
  40. 40.
    Davies FE, Raje N, Hideshima T, et al.: Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001, 98:210–216.PubMedCrossRefGoogle Scholar
  41. 41.
    Gupta D, Treon SP, Shima Y, et al.: Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001, 15:1950–1961.PubMedGoogle Scholar
  42. 42.
    Mahadevan D, List AF, Tate W, et al.: The immunomodulatory thalidomide analog CC5013 is a potent receptor tyrosine kinase (RTK) inhibitor that abolishes vascular endothelial growth factor (VEGF) trophic response in malignant myeloid progenitors. Leuk Res 2003, 27:S108–S109.Google Scholar
  43. 43.
    List A, Kurtin S, Roe DJ, et al.: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005, 352:549–557PubMedCrossRefGoogle Scholar
  44. 44.
    List A, Dewald G, Bennett J, et al.: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006, 355:1456–1465.PubMedCrossRefGoogle Scholar
  45. 45.
    Raza A, Reeves JA, Feldman EJ, et al.: Phase II study of lenalidomide in transfusion-dependent, low-and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2007, In press.Google Scholar
  46. 46.
    Buesche G, Dieck S, Giagounidis A, et al.: Anti-angiogenic in vivo effect of lenalidomide (CC-5013) in myelodysplastic syndrome with del(5q) chromosome abnormality and its relation to the course of disease [abstract]. Blood 2005, 106:113a.Google Scholar
  47. 47.
    List A, Beran M, DiPersio J, et al.: Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia 2003, 17:1499–1507.PubMedCrossRefGoogle Scholar
  48. 48.
    Miller WH Jr, Schipper HM, Lee JS, et al.: Mechanisms of action of arsenic trioxide. Cancer Res 2002, 62:3893–3903.PubMedGoogle Scholar
  49. 49.
    Lew YS, Brown SL, Griffin RJ, et al.: Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res 1999, 59:6033–6037.PubMedGoogle Scholar
  50. 50.
    Roboz GJ, Dias S, Lam G, et al.: Arsenic trioxide induces dose-and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 2000, 96:1525–1530.PubMedGoogle Scholar
  51. 51.
    Schiller GJ, Slack J, Hainsworth JD, et al.: Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 2006, 24:2456–2464.PubMedCrossRefGoogle Scholar
  52. 52.
    Vey N, Bosly A, Guerci A, et al.: Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol 2006, 24:2465–2471.PubMedCrossRefGoogle Scholar
  53. 53.
    Giles FJ, Stopeck AT, Silverman LR, et al.: SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003, 102:795–801.PubMedCrossRefGoogle Scholar
  54. 54.
    Giles FJ, Bellamy WT, Estrov Z, et al.: The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res 2006, 30:801–811.PubMedCrossRefGoogle Scholar
  55. 55.
    Gupta P, Sanford BL, Yu D, et al.: A phase II study of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B Study 10105 [abstract]. Blood 2006, 108:753a.Google Scholar
  56. 56.
    Parker J, Mufti GJ: Ras and myelodysplasia: lessons from the last decade. Semin Hematol 1996, 33:206–224.PubMedGoogle Scholar
  57. 57.
    Casey PJ, Solski PA, Der CJ, et al.: p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci U S A 1989, 86:8323–8327.PubMedCrossRefGoogle Scholar
  58. 58.
    Fenaux P, Raza A, Mufti GJ, et al.: A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate-to high-risk myelodysplastic syndrome. Blood 2007, 109:4158–4163.PubMedCrossRefGoogle Scholar
  59. 59.
    Delmas C, End D, Rochaix P, et al.: The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clin Cancer Res 2003, 9:6062–6068.PubMedGoogle Scholar
  60. 60.
    Izbicka E, Campos D, Carrizales G, et al.: Biomarkers of anticancer activity of R115777 (Tipifarnib, Zarnestra) in human breast cancer models in vitro. Anticancer Res 2005, 25:3215–3223.PubMedGoogle Scholar
  61. 61.
    Gu WZ, Tahir SK, Wang YC, et al.: Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo. Eur J Cancer 1999, 35:1394–1401.PubMedCrossRefGoogle Scholar
  62. 62.
    Desrosiers RR, Cusson MH, Turcotte S, et al.: Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration. Int J Cancer 2005, 114:702–712.PubMedCrossRefGoogle Scholar
  63. 63.
    Takada Y, Khuri FR, Aggarwal BB: Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappaB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappaB-regulated gene expression and up-regulation of apoptosis. J Biol Chem 2004, 279:26287–26299.PubMedCrossRefGoogle Scholar
  64. 64.
    Han JY, Oh SH, Morgillo F, et al.: Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J Natl Cancer Inst 2005, 97:1272–1286.PubMedCrossRefGoogle Scholar
  65. 65.
    Cortes J, Albitar M, Thomas D, et al.: Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003, 101:1692–1697.PubMedCrossRefGoogle Scholar
  66. 66.
    Mesa RA, Camoriano JK, Geyer SM, et al.: A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia 2007, 21:1964–1970.PubMedCrossRefGoogle Scholar
  67. 67.
    Gotlib J, Jamieson CHM, List A, et al.: Phase II study of bevacizumab (anti-vegf humanized monoclonal antibody) in patients with myelodysplastic syndrome (MDS): preliminary results [abstract]. Blood 2003, 102:425a. Abstract 1545.Google Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Division of HematologyStanford Cancer CenterStanfordUSA

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