Skip to main content

Advertisement

SpringerLink
Log in

Recent concepts of antiangiogenic therapy

  • Review Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

In 2004, a randomized, controlled phase III clinical trial showed that the addition of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, to conventional chemotherapy prolonged the survival of patients with metastatic colorectal cancer. A number of clinical trials are presently underway to test the utility of several angiogenic inhibitors against a variety of malignancies. The original concept of antiangiogenic therapy was the inhibition of outgrowth of new blood vessels; however, it soon became evident that bevacizumab could affect the vasculature through various mechanisms. Recent studies have shown that antiangiogenic agents can normalize the tumor vasculature and prevent the recruitment of endothelial progenitor cells from the bone marrow. Some preclinical studies have also shown that antiangiogenic agents prevent metastasis by modulating the premetastatic niche. Understanding these detailed mechanisms provides the rationale for combination therapy using antiangiogenic agents and cytotoxic chemotherapy, and will lead to more effective treatment strategies. In this review, we summarize the present understanding of the mechanisms of action of antiangiogenic agents and discuss the future prospects of antiangiogenic therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Kanai T, Konno H, Tanaka T, Baba M, Matsumoto K, Nakamura S, et al. Anti-tumor and anti-metastatic effects of human vascular endothelial growth factor neutralizing antibody on human colon and gastric carcinoma xenotransplanted orthotopically into nude mice. Int J Cancer 1998;77:933–936.

    Article  CAS  PubMed  Google Scholar 

  3. Konno H, Arai T, Tanaka T, Baba M, Matsumoto K, Kanai T, et al. Antitumor effect of a neutralizing antibody to vascular endothelial growth factor on liver metastasis of endocrine neoplasm. Jpn J Cancer Res 1998;89:933–939.

    CAS  PubMed  Google Scholar 

  4. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.

    Article  CAS  PubMed  Google Scholar 

  5. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci 2005;109:227–241.

    Article  CAS  PubMed  Google Scholar 

  6. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, et al. Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 2001;61:6400–6405.

    CAS  PubMed  Google Scholar 

  9. Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res 2007;67:2729–2735.

    Article  CAS  PubMed  Google Scholar 

  10. Miki C, Tanaka K, Inoue Y, Araki T, Ohi M, Mohri Y, et al. Perioperative host-tumor inflammatory interactions: a potential trigger for disease recurrence following a curative resection for colorectal cancer. Surg Today 2008;38:579–584.

    Article  PubMed  Google Scholar 

  11. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6:553–563.

    CAS  PubMed  Google Scholar 

  12. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  13. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008;319:195–198.

    Article  CAS  PubMed  Google Scholar 

  14. Bertolini F, Shaked Y, Mancuso P, Kerbel RS. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 2006;6:835–845.

    Article  CAS  PubMed  Google Scholar 

  15. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194–1201.

    Article  CAS  PubMed  Google Scholar 

  16. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820–827.

    Article  CAS  PubMed  Google Scholar 

  17. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006;313:1785–1787.

    Article  CAS  PubMed  Google Scholar 

  18. Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease. Cancer 2004;100:2491–2499.

    Article  CAS  PubMed  Google Scholar 

  19. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer 2005;5:423–435.

    Article  CAS  PubMed  Google Scholar 

  20. Furstenberger G, von Moos R, Lucas R, Thurlimann B, Senn HJ, Hamacher J, et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer 2006;94:524–531.

    Article  CAS  PubMed  Google Scholar 

  21. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–24.

    Article  CAS  PubMed  Google Scholar 

  22. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76–82.

    Article  CAS  PubMed  Google Scholar 

  23. Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell’Agnola C, Gobbi A, et al. Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res 2001;61:4341–4344.

    CAS  PubMed  Google Scholar 

  24. Mancuso P, Calleri A, Cassi C, Gobbi A, Capillo M, Pruneri G, et al. Circulating endothelial cells as a novel marker of angiogenesis. Adv Exp Med Biol 2003;522:83–97.

    PubMed  Google Scholar 

  25. Beaudry P, Force J, Naumov GN, Wang A, Baker CH, Ryan A, et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res 2005;11:3514–3522.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 2005;7:101–111.

    CAS  PubMed  Google Scholar 

  28. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for nonsmall-cell lung cancer. N Engl J Med 2006;355:2542–2550.

    Article  CAS  PubMed  Google Scholar 

  29. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666–2676.

    Article  CAS  PubMed  Google Scholar 

  30. Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–3129.

    Article  CAS  PubMed  Google Scholar 

  31. Senior K. Combination treatment improves breast-cancer survival. Lancet Oncol 2006;7:370.

    Article  PubMed  Google Scholar 

  32. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008;8:579–591.

    Article  CAS  PubMed  Google Scholar 

  33. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–134.

    Article  CAS  PubMed  Google Scholar 

  34. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390.

    Article  CAS  PubMed  Google Scholar 

  35. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–1338.

    Article  CAS  PubMed  Google Scholar 

  36. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–124.

    Article  CAS  PubMed  Google Scholar 

  37. Koehne C, Bajetta E, Lin E, Valle J, Van Cutsem E, Hecht J, et al. Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo. Proc Am Soc Clin Oncol 2007;4033a.

  38. Koehne C, Bajetta E, Lin E, Van Cutsem E, Hecht J, Douillard J, et al. Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2). Proc Am Soc Clin Oncol 2006;3508a.

  39. Ohta M, Kawabata T, Yamamoto M, Tanaka T, Kikuchi H, Hiramatsu Y, et al. TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model. Surg Today 2009;39:1046–1053.

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto M, Kikuchi H, Ohta M, Kawabata T, Hiramatsu Y, Kondo K, et al. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res 2008;68:9754–9762.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Hiroyuki Konno, Masayoshi Yamamoto & Manabu Ohta

Authors
  1. Hiroyuki Konno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayoshi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manabu Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Konno, H., Yamamoto, M. & Ohta, M. Recent concepts of antiangiogenic therapy. Surg Today 40, 494–500 (2010). https://doi.org/10.1007/s00595-009-4150-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-009-4150-2

Key words

Search

Navigation