Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition

Abstract

Contrary to initial expectations, angiogenesis inhibitors can cause toxicities in patients with cancer. The toxicity profiles of these inhibitors reflect the disturbance of growth factor signalling pathways that are important for maintaining homeostasis. Experiences with angiogenesis inhibitors in clinical trials indicate that short-term toxicities are mostly manageable. However, these agents will also be given in prolonged treatment strategies, so we need to anticipate possible long-term toxicities. In addition, understanding the molecular mechanisms involved in the toxicity of angiogenesis inhibition should allow more specific and more potent inhibitors to be developed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The various biological functions of VEGF.
Figure 2: Platelet–endothelial cell interactions and the anti-coagulatory activity of the quiescent endothelium.
Figure 3: Angiogenic growth factor stimulation of the endothelium causes concomitant activation of the coagulation cascade and angiogenesis.
Figure 4: Blood pressure regulation by the vascular system.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clin. Pract. Oncol. 3, 24–40 (2006).

    Article  CAS  Google Scholar 

  5. Saltz, L. B. et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Gastrointestinal Cancers Symp. abstract 238 (2007).

  6. Motzer, R. J. et al. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Motzer, R. J. et al. Sunitinib versus interferon a in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Ratain, M. J. et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 2505–2512 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Demetri, G. D. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368, 1329–1338 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Kim, D. W. et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J. Clin. Endocrinol. Metab. 91, 4070–4076 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Abrams, T. J., Lee, L. B., Murray, L. J., Pryer, N. K. & Cherrington, J. M. SU11248 inhibits KIT and platelet-derived growth factor receptor b in preclinical models of human small cell lung cancer. Mol. Cancer Ther. 2, 471–478 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Carlomagno, F. et al. BAY 43–9006 inhibition of oncogenic RET mutants. J. Natl Cancer Inst. 98, 326–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nature Rev. Drug Discov. 5, 835–844 (2006).

    Article  CAS  Google Scholar 

  14. Augustin, H. G., Kozian, D. H. & Johnson, R. C. Differentiation of endothelial cells: analysis of the constitutive and activated endothelial cell phenotypes. Bioessays 16, 901–906 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Denekamp, J. Vascular endothelium as the vulnerable element in tumours. Acta Radiol. Oncol. 23, 217–225 (1984).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Dekker, R. J. et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107, 4354–4363 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Folkman, J. & Kalluri, R. Cancer without disease. Nature 427, 787 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Verheul, H. M. & Pinedo, H. M. Inhibition of angiogenesis in cancer patients. Expert Opin. Emerg. Drugs 10, 403–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Bellamy, W. T. 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 97, 1427–1434 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166 (1998).

    CAS  PubMed  Google Scholar 

  22. Kuenen, B. C. et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler. Thromb. Vasc. Biol. 22, 1500–1505 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003).

    CAS  PubMed  Google Scholar 

  24. Wilhelm, S. M. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Gasparini, G., Longo, R., Fanelli, M. & Teicher, B. A. Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions. J. Clin. Oncol. 23, 1295–1311 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Kuenen, B. C. et al. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J. Clin. Oncol. 20, 1657–1667 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Mross, K. et al. Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. Eur. J. Cancer 43, 55–63 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Jubb, A. M., Oates, A. J., Holden, S. & Koeppen, H. Predicting benefit from anti-angiogenic agents in malignancy. Nature Rev. Cancer 6, 626–635 (2006).

    Article  CAS  Google Scholar 

  29. Cobleigh, M. A. et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin. Oncol. 30, 117–124 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Gordon, M. S. et al. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Margolin, K. et al. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Faivre, S. et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J. Clin. Oncol. 24, 25–35 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Fiedler, W. et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105, 986–993 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. O'Farrell, A. M. et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin. Cancer Res. 9, 5465–5476 (2003).

    CAS  PubMed  Google Scholar 

  35. Awada, A. et al. Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br. J. Cancer 92, 1855–1861 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baker, S. D. et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. J. Natl Cancer Inst. 94, 1883–1888 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Karp, J. E. et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-b-D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin. Cancer Res. 10, 3577–3585 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Motzer, R. J. et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295, 2516–2524 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Hurwitz, H. I., Honeycutt, W., Haley, S. & Favaro, J. Long-term treatment with bevacizumab for patients with metastatic colorectal cancer: case report. Clin. Colorectal Cancer 6, 66–69 (2006).

    Article  PubMed  Google Scholar 

  40. Ronnen, E. A., Kondagunta, G. V., Ginsberg, M. S., Russo, P. & Motzer, R. J. Long-term response with sunitinib for metastatic renal cell carcinoma. Urology 68, 672 e19–e20 (2006).

    Article  PubMed  Google Scholar 

  41. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Broxterman, H. J., Lankelma, J. & Hoekman, K. Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences. Drug Resist. Updat. 6, 111–127 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Drevs, J. et al. 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 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Robert, C., Faivre, S., Raymond, E., Armand, J. P. & Escudier, B. Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors? Ann. Intern. Med. 143, 313–314 (2005).

    Article  PubMed  Google Scholar 

  45. Herbst, R. S. & Sandler, A. B. Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab? Oncologist 9 (Suppl. 1), 19–26 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Kabbinavar, F. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Motzer, R. J., Hoosen, S., Bello, C. L. & Christensen, J. G. Sunitinib malate for the treatment of solid tumours: a review of current clinical data. Expert Opin. Investig. Drugs 15, 553–561 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Scappaticci, F. A. et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J. Surg. Oncol. 91, 173–180 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. McCarty, M. E. & Ellis, L. M. Mechanisms of anti-angiogenic tyrosine kinase inhibition on wound healing — the obvious and not so obvious. Cancer Biol. Ther. 1, 127–129 (2002).

    Article  PubMed  Google Scholar 

  50. Duan, W. R., Patyna, S., Kuhlmann, M. A., Li, S. & Blomme, E. A. A multitargeted receptor tyrosine kinase inhibitor, SU6668, does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice. J. Invest. Surg. 19, 245–254 (2006).

    Article  PubMed  Google Scholar 

  51. Haroon, Z. A. et al. SU5416 delays wound healing through inhibition of TGF-β 1 activation. Cancer Biol. Ther. 1, 121–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Ma, L. et al. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc. Natl Acad. Sci. USA 98, 6470–6475 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sugrue, M. M. et al. Safety and effectiveness of bevacizumab plus chemotherapy in elderly patients with mCRC: Results from the BRiTE registry. Gastrointestinal Cancers Symp. abstract 345 (2007).

  54. Wright, J. D. et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: a retrospective analysis. Cancer 107, 83–89 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Lordick, F., Geinitz, H., Theisen, J., Sendler, A. & Sarbia, M. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int. J. Radiat. Oncol. Biol. Phys. 64, 1295–1298 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Verheul, H. M. et al. Platelet: transporter of vascular endothelial growth factor. Clin. Cancer Res. 3, 2187–2190 (1997).

    CAS  PubMed  Google Scholar 

  58. Banks, R. E. et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br. J. Cancer 77, 956–964 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Weltermann, A. et al. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler. Thromb. Vasc. Biol. 19, 1757–1760 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Verheul, H. M. et al. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 96, 4216–4221 (2000).

    CAS  PubMed  Google Scholar 

  61. Rhee, J. S. et al. The functional role of blood platelet components in angiogenesis. Thromb. Haemost. 92, 394–402 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Kisucka, J. et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc. Natl Acad. Sci. USA 103, 855–860 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Selheim, F., Holmsen, H. & Vassbotn, F. S. Identification of functional VEGF receptors on human platelets. FEBS Lett. 512, 107–110 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Okuda, Y. et al. Hypoxia and endothelin-1 induce VEGF production in human vascular smooth muscle cells. Life Sci. 63, 477–484 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Reinmuth, N. et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 15, 1239–1241 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. te Velde, E. A., Kusters, B., Maass, C., de Waal, R. & Borel Rinkes, I. H. Histological analysis of defective colonic healing as a result of angiostatin treatment. Exp. Mol. Pathol. 75, 119–123 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Nash, G. F., Walsh, D. C. & Kakkar, A. K. The role of the coagulation system in tumour angiogenesis. Lancet Oncol. 2, 608–613 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Zucker, S. et al. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int. J. Cancer 75, 780–786 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Koomagi, R. & Volm, M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int. J. Cancer 79, 19–22 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Shoji, M. et al. Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. Am. J. Pathol. 152, 399–411 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Pawlinski, R., Pedersen, B., Erlich, J. & Mackman, N. Role of tissue factor in haemostasis, thrombosis, angiogenesis and inflammation: lessons from low tissue factor mice. Thromb. Haemost. 92, 444–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Ma, L. et al. In vitro procoagulant activity induced in endothelial cells by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy. Cancer Res. 65, 5365–5373 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Rickles, F. R. Mechanisms of cancer-induced thrombosis in cancer. Pathophysiol. Haemost. Thromb. 35, 103–110 (2006).

    Article  PubMed  Google Scholar 

  74. Heymach, J. V. et al. Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin. Cancer Res. 10, 5732–5740 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Pearson, J. D. Normal endothelial cell function. Lupus 9, 183–188 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Cines, D. B. et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91, 3527–3561 (1998).

    CAS  PubMed  Google Scholar 

  77. Taraseviciene-Stewart, L. et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427–438 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Bombeli, T., Karsan, A., Tait, J. F. & Harlan, J. M. Apoptotic vascular endothelial cells become procoagulant. Blood 89, 2429–2442 (1997).

    CAS  PubMed  Google Scholar 

  79. Hathcock, J. J. Flow effects on coagulation and thrombosis. Arterioscler. Thromb. Vasc. Biol. 26, 1729–1737 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Bergmeier, W. et al. The role of platelet adhesion receptor GPIbα far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc. Natl Acad. Sci. USA 103, 16900–16905 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kilickap, S., Abali, H. & Celik, I. Bevacizumab, bleeding, thrombosis, and warfarin. J. Clin. Oncol. 21, 3542 (2003).

    Article  PubMed  Google Scholar 

  82. Meyer, T. et al. Targeting angiogenesis in cancer: bevacizumab-induced platelet activation as a possible cause for unexpected arterial thromboembolic events in clinical trials. ASH annual meeting, abstract 1091 (2006).

  83. Hong, C. C., Peterson, Q. P., Hong, J. Y. & Peterson, R. T. Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling. Curr. Biol. 16, 1366–1372 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Veronese, M. L. et al. Mechanisms of hypertension associated with BAY 43–9006. J. Clin. Oncol. 24, 1363–1369 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Sane, D. C., Anton, L. & Brosnihan, K. B. Angiogenic growth factors and hypertension. Angiogenesis 7, 193–201 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Sica, D. A. Angiogenesis inhibitors and hypertension: an emerging issue. J. Clin. Oncol. 24, 1329–1331 (2006).

    Article  PubMed  Google Scholar 

  87. Miller, K. D. et al. 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 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Hariawala, M. D. et al. VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts. J. Surg. Res. 63, 77–82 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Li, B. et al. KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF. Hypertension 39, 1095–1100 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Eppler, S. M. et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin. Pharmacol. Ther. 72, 20–32 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Scotland, R. S. et al. Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double-knockout mice: key role for endothelium-derived hyperpolarizing factor in the regulation of blood pressure in vivo. Circulation 111, 796–803 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Gelinas, D. S., Bernatchez, P. N., Rollin, S., Bazan, N. G. & Sirois, M. G. Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways. Br. J. Pharmacol. 137, 1021–1030 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Umemoto, S. et al. Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo. Hypertens Res. 29, 179–186 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Yang, R. et al. Exaggerated hypotensive effect of vascular endothelial growth factor in spontaneously hypertensive rats. Hypertension 39, 815–820 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Ciuffetti, G. et al. Capillary rarefaction and abnormal cardiovascular reactivity in hypertension. J. Hypertens. 21, 2297–2303 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Matsuura, A. et al. Vascular endothelial growth factor increases endothelin-converting enzyme expression in vascular endothelial cells. Biochem. Biophys. Res. Commun. 235, 713–716 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Williams, G. H. in Harrisons principles of internal medicine 246 (McGraw–Hill, USA, 2004).

    Google Scholar 

  98. Yau, T. M. et al. Maximizing ventricular function with multimodal cell-based gene therapy. Circulation 112, I123–I128 (2005).

    PubMed  Google Scholar 

  99. Tam, C. S. et al. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am. J. Hematol. 77, 72–76 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Ozcan, C., Wong, S. J. & Hari, P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N. Engl. J. Med. 354, 980–982 (2006).

    Article  PubMed  Google Scholar 

  101. Glusker, P., Recht, L. & Lane, B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N. Engl. J. Med. 354, 980–982 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Govindarajan, R., Adusumilli, J., Baxter, D. L., El-Khoueiry, A. & Harik, S. I. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43–9006. J. Clin. Oncol. 24, e48 (2006).

    Article  PubMed  Google Scholar 

  103. Desai, J. et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal tumors. Ann. Int. Med. 145, 660–664 (2006).

    Article  PubMed  Google Scholar 

  104. Gerard, A. C. et al. Structural changes in the angiofollicular units between active and hypofunctioning follicles align with differences in the epithelial expression of newly discovered proteins involved in iodine transport and organification. J. Clin. Endocrinol. Metab. 87, 1291–1299 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Wang, J. F. et al. Presence and possible role of vascular endothelial growth factor in thyroid cell growth and function. J. Endocrinol. 157, 5–12 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Willett, C. G. et al. 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. 23, 8136–8139 (2005).

    Article  PubMed  Google Scholar 

  107. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Kamba, T. et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H560–H576 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. de Vriese, A. S. et al. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J. Am. Soc. Nephrol. 12, 993–1000 (2001).

    CAS  Google Scholar 

  110. Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605–12608 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Hara, A. et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int. 69, 1986–1995 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Eremina, V. et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J. Am. Soc. Nephrol. 17, 724–735 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Yang, C. C., Chu, K. C. & Yeh, W. M. Expression of vascular endothelial growth factor in renal cell carcinoma is correlated with cancer advancement. J. Clin. Lab. Anal. 17, 85–89 (2003).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Jacobsen, J. et al. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 93, 297–302 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Masuda, Y. et al. Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am. J. Pathol. 159, 599–608 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Guan, F., Villegas, G., Teichman, J., Mundel, P. & Tufro, A. Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP. Am. J. Physiol. Renal Physiol. 291, F422–F428 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Katoh, O., Tauchi, H., Kawaishi, K., Kimura, A. & Satow, Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 55, 5687–5692 (1995).

    CAS  PubMed  Google Scholar 

  119. Peichev, M. et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 95, 952–958 (2000).

    CAS  PubMed  Google Scholar 

  120. Bellamy, W. T. Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies. Semin. Oncol. 28, 551–559 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Mohle, R., Green, D., Moore, M. A., Nachman, R. L. & Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ohm, J. E. & Carbone, D. P. VEGF as a mediator of tumor-associated immunodeficiency. Immunol. Res. 23, 263–272 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Robert, C. et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 6, 491–500 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Strumberg, D. et al. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: is rash associated with treatment outcome? Eur. J. Cancer 42, 548–556 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Tsao, A. S., Kantarjian, H., Cortes, J., O'Brien, S. & Talpaz, M. Imatinib mesylate causes hypopigmentation in the skin. Cancer 98, 2483–2487 (2003).

    Article  PubMed  Google Scholar 

  126. Gimbrone, M. A., Jr. et al. Preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium. Nature 222, 33–36 (1969).

    Article  PubMed  Google Scholar 

  127. Hanson, S. R. & Slichter, S. J. Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. Blood 66, 1105–1109 (1985).

    CAS  PubMed  Google Scholar 

  128. Slichter, S. J. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus. Med. Rev. 18, 153–167 (2004).

    Article  PubMed  Google Scholar 

  129. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  Google Scholar 

  130. Podar, K. et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc. Natl Acad. Sci. USA 103, 19478–19483 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Goodlad, R. A. et al. Inhibiting vascular endothelial growth factor receptor-2 signaling reduces tumor burden in the ApcMin/+ mouse model of early intestinal cancer. Carcinogenesis 27, 2133–2139 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Wood, J. M. 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. 60, 2178–2189 (2000).

    CAS  PubMed  Google Scholar 

  133. Huang, J. et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc. Natl Acad. Sci. USA 100, 7785–7790 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. McCarty, M. F. et al. ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol. Cancer Ther. 3, 1041–1048 (2004).

    CAS  PubMed  Google Scholar 

  135. Polverino, A. et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 66, 8715–8721 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Baffert, F. et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am. J. Physiol. Heart Circ. Physiol. 290, H547–H559 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

H.V. is a recipient of the American Society of Clinical Oncology (ASCO) Young Investigator's award 2006 and of a Drug Development fellowship at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institution. This work was supported in part by The Adriana van Coevorden Society (H.V.) and for a major part by the Spinoza award (H.M.P.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Herbert M. Pinedo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

US National Cancer Institute

Glossary

Acral erythema

Redness of the most distal extremities caused by capillary congestion (a general sign of inflammation).

Baroreceptors

Located in the carotid arteries in the neck, these receptors are stretched by high blood pressure, reducing the activation of the vasomotor centre. They also activate the vasomotor centre in response to low blood pressure.

Dendritic cells

Immune cells that process antigens and present them to other immune cells.

Encephalopathy

Alteration in brain function and/or structure. Common symptoms include progressive loss of memory and cognitive ability, subtle personality changes, inability to concentrate, lethargy and progressive loss of consciousness.

Gastrointestinal perforations

Can occur in the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity.

Glomerulus

A capillary bed surrounded by the Bowman's capsule in the kidney, which regulates blood filtration and urine generation.

Ischaemia

An inadequate blood supply to an organ.

Left ventricular ejection fraction

The fraction of blood pumped out of the left ventricle with each heart beat.

Leukopenia and lymphopenia

A low leukocyte or lymphocyte count in the circulating blood, both of which increase the risk of infections.

Megakaryocytes

The precursor cells of platelets, located in the bone marrow.

Perivascular cells

Cells that surround vessels, including pericytes, myofibroblasts and smooth muscle cells.

Podocytes

Cells that form the visceral epithelium in the kidney and are involved in the glomerular filtration barrier.

Reversible posterior leukoencephalopathy syndrome

A rapidly evolving neurological syndrome. The underlying mechanism seems to be related to an increased permeability and reactivity of brain vasculature.

Subungual splinter bleeding

A small amount of bleeding that occurs under a finger or toe nail.

Thrombocytopenia

A low platelet count in the circulating blood.

Vascular resistance

The resistance to flow that must be overcome to push blood though a vessel; determined by diameter, stiffness and length of the vessel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verheul, H., Pinedo, H. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7, 475–485 (2007). https://doi.org/10.1038/nrc2152

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2152

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing