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.

  • Review Article
  • Published:

The anti-angiogenic basis of metronomic chemotherapy

Nature Reviews Cancer volume 4, pages 423–436 (2004)Cite this article

Key Points

  • Conventional cytotoxic anticancer drugs have anti-angiogenic effects, which could contribute to their antitumour efficacy.

  • The anti-angiogenic effects of chemotherapy seem to be optimized by administering such drugs 'metronomically' — in small doses on a frequent schedule (daily, several times a week, or weekly) in an uninterrupted manner, for prolonged periods.

  • Conventional chemotherapy, which is administered at more toxic 'maximum tolerated doses', requires 2–3-week breaks between successive cycles of therapy. This seems to counteract the potential for sustained, therapeutically effective anti-angiogenic effects.

  • In preclinical models, metronomic chemotherapy can be effective in treating tumours in which the cancer cells have developed resistance to the same chemotherapeutics. This also has the advantage of being less acutely toxic, therefore making more prolonged treatments possible.

  • The efficacy of metronomic chemotherapy can be significantly increased when administered in combination with anti-angiogenic drugs, such as antibodies against vascular endothelial growth factor (VEGF) or VEGF receptor 2.

  • Some metronomic-chemotherapy regimens induce sustained suppression of circulating endothelial progenitor cells and increase the levels of the endogenous angiogenesis inhibitor thrombospondin 1, both of which can suppress neovascularization.

  • Clinical trials are under way to test several combinations of metronomic chemotherapy and anti-angiogenic drugs.

Abstract

In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Different therapeutic regimens.
Figure 2: Possible mechanisms of the anti-angiogenic basis of metronomic chemotherapy.

Similar content being viewed by others

References

  1. Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Leaf, C. Why we're losing the war on cancer (and how to win it). Fortune 149, 77–97 (2004).

    Google Scholar 

  3. Hanahan, D., Bergers, G. & Bergsland, E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Invest. 105, 1045–1047 (2000). An insightful commentary in which the term 'metronomic' was coined to describe prolonged therapy using frequent administration of low doses of chemotherapy as an anti-angiogenic treatment strategy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gasparini, G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol. 2, 733–740 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Kamen, B. A., Rubin, E., Aisner, J. & Glatstein, E. High-time chemotherapy or high time for low dose. J. Clin. Oncol. 18, 2935–2937 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Kerbel, R. S., Klement, G., Pritchard, K. I. & Kamen, B. A. Continuous low-dose anti-angiogenic (metronomic) chemotherapy: from the research laboratory into the oncology clinic. Ann. Oncol. 13, 12–15 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Nieto, Y. The verdict is not in yet. Analysis of the randomized trials of high-dose chemotherapy for breast cancer. Haematologica 88, 201–211 (2003).

    CAS  PubMed  Google Scholar 

  8. Roche, H., Viens, P., Biron, P., Lotz, J. P. & Asselain, B. High-dose chemotherapy for breast cancer: the French PEGASE experience. Cancer Control 10, 42–47 (2003).

    Article  PubMed  Google Scholar 

  9. Piccart-Gebhart, M. J. Mathematics and oncology: a match for life? J. Clin. Oncol. 21, 1425–1428 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Tuma, R. S. Dosing study seen as victory for clinical trials, mathematical models. J. Natl Cancer Inst. 95, 254–255 (2003).

    Article  PubMed  Google Scholar 

  11. Citron, M. L. et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin. Oncol. 21, 1431–1439 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Lokich, J. Phase I clinical trial of weekly combined paclitaxel plus docetaxel in patients with solid tumors. Cancer 89, 2309–2314 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Burstein, H. J. et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J. Clin. Oncol. 18, 1212–1219 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Aihara, T., Kim, Y. & Takatsuka, Y. Phase II study of weekly docetaxel in patients with metastatic breast cancer. Ann. Oncol. 13, 286–292 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Tulpule, A. et al. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 95, 147–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bertolini, F. et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 63, 4342–4346 (2003). A possible explanation for the repair of the tumour neovasculature during the prolonged drug-free break periods between cycles of MTD chemotherapy. Repair is mediated through mobilization of circulating endothelial progenitor cells, which is circumvented by metronomic dosing.

    CAS  PubMed  Google Scholar 

  18. Bello, L. et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo. Cancer Res. 61, 7501–7506 (2001). An excellent preclinical study comparing the effects of a metronomic protocol using two different chemotherapeutic drugs (carboplatin and etoposide) to a more conventional, high-dose regimen of the same drugs. It showed improved survival times for patients on the metronomic regimen, including when this was combined with an anti-angiogenic agent for the treatment of a rodent model of glioma.

    CAS  PubMed  Google Scholar 

  19. Man, S. et al. Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 62, 2731–2735 (2002). A simple, convenient and humane method of administering low doses of a drug (cyclophosphamide) on a daily basis over long periods to test metronomic chemotherapy in mouse models of cancer.

    CAS  PubMed  Google Scholar 

  20. Hahnfeldt, P., Folkman, J. & Hlatky, L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J. Theor. Biol. 220, 545–554 (2003).

    Article  PubMed  Google Scholar 

  21. Stoll, B. R., Migliorini, C., Kadambi, A., Munn, L. L. & Jain, R. K. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for anti-angiogenic therapy. Blood 102, 2555–2561 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000). A seminal study that first defined the basic principles of metronomic or 'anti-angiogenic' chemotherapy and outlined a strategy for treating drug-resistant tumours by altering the dosing and scheduling of chemotherapy, so as to target the neovasculature of the tumour more effectively.

    CAS  PubMed  Google Scholar 

  23. Miller, K. D., Sweeney, C. J. & Sledge, G. W. Redefining the target: chemotherapeutics as antiangiogenics. J. Clin. Oncol. 19, 1195–1206 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Hurwitz, H. et al. Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. Proc. Am. Soc. Clin. Oncol. 21, A3646 (2003).

    Google Scholar 

  25. Hurwitz, H. et al. Addition of bevacizumab (rhuMab VEGF) to bolus IFL in the first line treatment of patients with metastatic colorectal cancer: results of a randomized phase III trial. N. Engl. J. Med. (in the press). The results of a pivotal randomized Phase III clinical trial in which bevacizumab, combined with a standard chemotherapy regimen, significantly improved the survival times of patients with advanced-stage metastatic colorectal carcinoma. This trial led to the approval of bevacizumab by the Food and Drug Administration on 26 February, 2004.

  26. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Eberhard, A. et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388–1393 (2000).

    CAS  PubMed  Google Scholar 

  28. Crawford, J. et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N. Engl. J. Med. 325, 164–170 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Kerbel, R. S. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. BioEssays 13, 31–36 (1991). A commentary that first outlined the concept that it should be possible to treat drug-resistant tumours by virtue of the effects of chemotherapy on the dividing endothelial cells of the genetically stable, growing neovasculature of a tumour.

    Article  CAS  PubMed  Google Scholar 

  30. Sweeney, C. J. et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 61, 3369–3372 (2001).

    CAS  PubMed  Google Scholar 

  31. Tran, J. et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl Acad. Sci. USA 99, 4349–4354 (2002). A study showing that VEGF can induce the equivalent of a multidrug-resistant phenotype in human vascular endothelial cells in vitro . This is because of the upregulation of the anti-apoptotic effector survivin when such cells are exposed to modest concentrations of the drugs in the presence of VEGF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takahashi, N., Haba, A., Matsuno, F. & Seon, B. K. Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res. 61, 7846–7854 (2001).

    CAS  PubMed  Google Scholar 

  33. Hamano, Y. et al. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res. 64, 1570–1574 (2004). Another important study showing that the antitumour effects of metronomic cyclophosphamide are mediated indirectly through induction of thrombospondin-1, produced by tumour cells and infiltrating stromal cells in tumours (B16 melanomas).

    Article  CAS  PubMed  Google Scholar 

  34. Bocci, G., Francia, G., Man, S., Lawler, J. & Kerbel, R. S. Thrombospondin-1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc. Natl Acad. Sci. USA 100, 12917–12922 (2003). First study to show an indirect mechanism that accounted for the anti-angiogenic effects induced by low-dose metronomic chemotherapy. This might be a paradigm for how some other angiogenesis inhibitors work.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Emmenegger, U. et al. A comparative analysis of low dose metronomic cyclophosphamide reveals absent or low grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens. Cancer Res. (in the press).

  36. Gately, S. & Kerbel, R. Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J. 7, 427–436 (2001).

    CAS  PubMed  Google Scholar 

  37. Kakolyris, S. et al. Treatment of non-small-cell lung cancer with prolonged oral etoposide. Am. J. Clin. Oncol. 21, 505–508 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Alvarez, A. et al. Weekly taxol (T) in patients who had relapsed or remained stable with T in a 21 day schedule. Proc. Am. Soc. Clin. Oncol. 17, A188 (1998).

    Google Scholar 

  39. Fennelly, D. et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J. Clin. Oncol. 15, 187–192 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Greco, F. A. Docetaxel (Taxotere) administered in weekly schedules. Semin. Oncol. 26, 28–31 (1999).

    CAS  PubMed  Google Scholar 

  41. Link, M. P., Shuster, J. J., Donaldson, S. S., Berard, C. W. & Murphy, S. B. Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N. Engl. J. Med. 337, 1259–1266 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Kamen, B. A. Why more 6-mercaptopurine? Semin. Hematol. 28, 12–14 (1991).

    CAS  PubMed  Google Scholar 

  43. Crist, W. M. et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J. Clin. Oncol. 19, 3091–3102 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Grundy, P. E. et al. Principles and practice of pediatric oncology (eds Pizzo, P. A. & Poplack, D. G.) 865–893 (Lippincott Williams and Wilkins, Philadelphia, 2002).

    Google Scholar 

  45. Camitta, B. M. & Kamen, B. A. Childhood acute lymphoblastic leukemia (ed. Pui, C. H.) 357–364 (Human Press Ltd, Totowa, New Jersey, 2003).

    Google Scholar 

  46. Joussen, A. M., Kruse, F. E., Volcker, H. E. & Kirchhof, B. Topical application of methotrexate for inhibition of corneal angiogenesis. Graefes Arch. Clin. Exp. Ophthalmol. 237, 920–927 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Hirata, S., Matsubara, T., Saura, R., Tateishi, H. & Hirohata, K. Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low-dose methotrexate. Arthritis Rheum. 32, 1065–1073 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Presta, M. et al. Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process. Cancer Res. 59, 2417–2424 (1999).

    CAS  PubMed  Google Scholar 

  49. Colleoni, M. et al. Low dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann. Oncol. 13, 73–80 (2002). Description of a Phase II clinical trial of metronomic chemotherapy involving prolonged administration of daily oral low-dose cyclophosphamide and low-dose methotrexate, with no breaks, to treat patients with advanced metastatic breast cancer. This result has spawned several other clinical trials, many involving addition of an anti-angiogenic drug.

    Article  CAS  PubMed  Google Scholar 

  50. Garber, K. Could less be more? Low-dose chemotherapy goes on trial. J. Natl. Cancer Inst. 94, 82–84 (2002).

    Article  PubMed  Google Scholar 

  51. Spieth, K., Kaufmann, R. & Gille, J. Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study. Cancer Chemother. Pharmacol. 52, 377–382 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Glode, L. M. et al. Metronomic therapy with cyclophosphamide and dexamethasone for prostate cancer. Cancer 98, 1643–1648 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Witte, L. et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 17, 155–161 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Alon, T. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Med. 1, 1024–1028 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Benjamin, L. E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gerber, H. P. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 273, 30336–30343 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Nor, J. E. & Polverini, P. J. Role of endothelial cell survival and death signals in angiogenesis. Angiogenesis 3, 101–116 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mandriota, S. J. et al. Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J. Biol. Chem. 270, 9709–9716 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Tran, J. et al. Marked induction of the IAP family anti-apoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem. Biophys. Res. Commun. 264, 781–788 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Mesri, M. et al. Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am. J. Pathol. 158, 1757–1765 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Castilla, M. A. et al. Role of vascular endothelial growth factor (VEGF) in endothelial cell protection against cytotoxic agents. Life Sci. 67, 1003–1013 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Gorski, D. H. et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 59, 3374–3378 (1999).

    CAS  PubMed  Google Scholar 

  63. Teicher, B. A., Sotomayor, E. A. & Huang, Z. D. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res. 52, 6702–6704 (1992).

    CAS  PubMed  Google Scholar 

  64. Kakeji, Y. & Teicher, B. A. Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents. Invest. New Drugs 15, 39–48 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Klement, G. et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug resistant human breast cancer xenograft. Clin. Cancer Res. 8, 221–232 (2002).

    CAS  PubMed  Google Scholar 

  66. Tashiro, T. et al. Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses. Cancer Chemother. Pharmacol. 24, 187–192 (1989).

    Article  CAS  PubMed  Google Scholar 

  67. Inaba, M. et al. Evaluation of antitumor activity in a human breast tumor/nude mouse model with a special emphasis on treatment dose. Cancer 64, 1577–1582 (1989).

    Article  CAS  PubMed  Google Scholar 

  68. Soffer, S. Z. et al. Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor. J. Pediatr. Surg. 36, 1177–1181 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Soffer, S. Z. et al. Novel use of an established agent: Topotecan is anti-angiogenic in experimental Wilms tumor. J. Pediatr. Surg. 36, 1781–1784 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Zhang, L. et al. Combined anti-fetal liver kinase 1 monoclonal antibody and continuous low-dose Doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis. Cancer Res. 62, 2034–2042 (2002).

    CAS  PubMed  Google Scholar 

  71. Abraham, D., Abri, S., Hofmann, M., Holtl, W. & Aharinejad, S. Low dose carboplatin combined with angiostatic agents prevents metastasis in human testicular germ cell tumor xenografts. J. Urol. 170, 1388–1393 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Svensson, A., Backman, U., Jonsson, E., Larsson, R. & Christofferson, R. CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs. Pediatr. Res. 51, 607–611 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Petrangolini, G. et al. Antiangiogenic effects of the novel camptothecin ST1481 (gimatecan) in human tumor xenografts. Mol. Cancer Res. 1, 863–870 (2003).

    CAS  PubMed  Google Scholar 

  74. Yonekura, K. et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin. Cancer Res. 5, 2185–2191 (1999).

    CAS  PubMed  Google Scholar 

  75. Yu, J. L., Rak, J. W., Coomber, B. L., Hicklin, D. J. & Kerbel, R. S. Effect of p53 status on tumor response to antiangiogenic therapy. Science 295, 1526–1528 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Huang, J. et al. Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol. Cancer Res. 2, 36–42 (2004).

    CAS  PubMed  Google Scholar 

  77. Belotti, D. et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin. Cancer Res. 2, 1843–1849 (1996).

    CAS  PubMed  Google Scholar 

  78. Bocci, G., Nicolaou, K. C. & Kerbel, R. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 62, 6938–6943 (2002). Selective inhibition of human endothelial-cell proliferation or induction of apoptosis was detected only after a prolonged exposure to very low concentrations of a number of different chemotherapeutic drugs, including taxanes and alkylating agents.

    CAS  PubMed  Google Scholar 

  79. Vacca, A. et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 94, 4143–4155 (1999). One of the first studies to show that ultra-low concentrations of the conventional chemotherapeutic drug vinblastine could selectively affect endothelial-cell functions relevant to angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  80. Wang, J., Lou, P., Lesniewski, R. & Henkin, J. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs 14, 13–19 (2003). An important study showing that low concentrations of paclitaxel selectively inhibit human vascular endothelial-cell proliferation in vitro , whereas non-endothelial cell types were inhibited by higher drug concentrations.

    Article  PubMed  Google Scholar 

  81. Grant, D. S., Williams, T. L., Zahaczewsky, M. & Dicker, A. P. Comparison of antiangiogenic activities using paclitaxel (taxol) and docetaxel (taxotere). Int. J. Cancer 104, 121–129 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Ng, S. S., Figg, W. D. & Sparreboom, A. Taxane-mediated antiangiogenesis in vitro: influence of formulation vehicles and binding proteins. Cancer Res. 64, 821–824 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. de Fraipont, F., Nicholson, A. C., Feige, J. J. & Van Meir, E. G. Thrombospondins and tumor angiogenesis. Trends. Mol. Med. 7, 401–407 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Lawler, J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J. Cell Mol. Med. 6, 1–12 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dawson, D. W. et al. CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol. 138, 707–717 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Guo, N., Krutzsch, H. C., Inman, J. K. & Roberts, D. D. Thrombospondin 1 and type 1 repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res. 57, 1735–1742 (1997).

    CAS  PubMed  Google Scholar 

  87. Jimenez, B. et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature Med. 6, 41–48 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Gupta, K., Gupta, P., Wild, R., Ramakrishnan, S. & Hebbel, R. P. Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis. Angiogenesis 3, 147–158 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Viloria-Petit, A. M. et al. Neutralizing antibodies against EGF and ErbB-2/neu receptor tyrosine kinases down-regulate VEGF production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am. J. Pathol. 151, 1523–1530 (1997).

    Google Scholar 

  90. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nature Rev. Cancer 2, 826–835 (2002).

    Article  CAS  Google Scholar 

  94. Ruzinova, M. B. et al. Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell 4, 277–289 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Sikder, H. et al. Disruption of Id1 reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell 4, 291–299 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Med. 5, 434–438 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Heeschen, C. et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102, 1340–1346 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Muta, M. et al. Impact of vasculogenesis on solid tumor growth in a rat model. Oncol. Rep. 10, 1213–1218 (2003).

    PubMed  Google Scholar 

  100. Brower, V. Epoetin for cancer patients: a boon or a danger? J. Natl Cancer Inst. 95, 1820–1821 (2004).

    Article  Google Scholar 

  101. Masferrer, J. L. et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60, 1306–1311 (2000).

    CAS  PubMed  Google Scholar 

  102. Gately, S. & Kerbel, R. Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. Prog. Exp. Tumor Res. 37, 179–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. DiPaola, R. S., Durivage, H. J. & Kamen, B. A. High time for low-dose prospective clinical trials. Cancer 98, 1559–1561 (2003).

    Article  PubMed  Google Scholar 

  104. Mancuso, P. et al. Circulating endothelial cells in preclinical cancer models and in cancer patients: origin, kinetics and viability after conventional-dose or metronomic chemotherapy. Proc. Am. Assoc. Cancer Res. A2051 (2003).

  105. 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 

  106. Ben-Efraim, S. Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity. Curr. Drug Targets 2, 197–212 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Matar, P., Guillermo, G., Celoria, C., Font, M. T. & Scharovsky, O. G. Antimetastatic effect of a single-low dose of cyclophosphamide on a rat lymphoma. J. Exp. Clin. Cancer Res. 14, 59–63 (1995).

    CAS  Google Scholar 

  108. Hermans, I. F., Chong, T. W., Palmowski, M. J., Harris, A. L. & Cerundolo, V. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res. 63, 8408–8413 (2003). An important study illustrating the potential benefits of combining a non-immunosuppressive metronomic weekly cyclophosphamide regimen with an immunotherapeutic approach to treat cancer. This circumvents the contra-indicated use of immunosuppresive MTD cytotoxic drug regimens with immunotherapy.

    CAS  PubMed  Google Scholar 

  109. Dunussi-Joannopoulos, K. The combination of chemotherapy and systemic immunotherapy and the concept of cure in murine leukemia and lymphoma. Leuk. Lymphoma 43, 2075–2082 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Wu, L. & Tannock, I. F. Repopulation in murine breast tumors during and after sequential treatments with cyclophosphamide and 5-fluorouracil. Cancer Res. 63, 2134–2138 (2003).

    CAS  PubMed  Google Scholar 

  111. Rubie, H. et al. Localised and unresectable neuroblastoma in infants: excellent outcome with low-dose primary chemotherapy. Br. J. Cancer 89, 1605–1609 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Azzarelli, A. et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer 92, 1259–1264 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Lamont, E. B. & Schilsky, R. L. The oral fluoropyrimidines in cancer chemotherapy. Clin. Cancer Res. 5, 2289–2296 (1999).

    CAS  PubMed  Google Scholar 

  114. Hoff, P. M., Pazdur, R., Benner, S. E. & Canetta, R. UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs 9, 479–490 (1998).

    CAS  PubMed  Google Scholar 

  115. Friedman, M. Of what value is uracil/tegafur plus leucovorin to colorectal cancer patients? J. Clin. Oncol. 20, 3574–3575 (2002).

    Article  PubMed  Google Scholar 

  116. Kato, H. et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N. Engl. J. Med. 350, 1713–1721 (2004). The results of an important Phase III trial to test adjuvant chemotherapy in patients with early stage lung cancer using a 5-fluoruracil prodrug called uracil plus tegafur. This drug was administered orally at low dose every day for two years, with no breaks. This could be an example, in retrospect, of a metronomic chemotherapy regimen with validated efficacy.

    Article  CAS  PubMed  Google Scholar 

  117. Yonekura, K. et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin. Cancer Res. 5, 2185–2191 (1999).

    CAS  PubMed  Google Scholar 

  118. Newlands, E. S., Stevens, M. F., Wedge, S. R., Wheelhouse, R. T. & Brock, C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat. Rev. 23, 35–61 (1997).

    Article  CAS  PubMed  Google Scholar 

  119. Kurzen, H., Schmitt, S., Naher, H. & Mohler, T. Inhibition of angiogenesis by non-toxic doses of temozolomide. Anticancer Drugs 14, 515–522 (2004).

    Article  Google Scholar 

  120. Niitsu, N. & Umeda, M. Evaluation of long-term daily administration of oral low-dose etoposide in elderly patients with relapsing or refractory non-Hodgkin's lymphoma. Am. J. Clin. Oncol. 20, 311–314 (1997).

    Article  CAS  PubMed  Google Scholar 

  121. Braybrooke, J. P. et al. A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis. Clin. Cancer Res. 6, 4697–4704 (2000).

    CAS  PubMed  Google Scholar 

  122. Danson, S. et al. Randomized phase II study of temozolomide given every 8 hours or daily with either interferon α-2b or thalidomide in metastatic malignant melanoma. J. Clin. Oncol. 21, 2551–2557 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Hwu, W. J. et al. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J. Clin. Oncol. 21, 3351–3356 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Malingre, M. M., Beijnen, J. H. & Schellens, J. H. Oral delivery of taxanes. Invest. New Drugs 19, 155–162 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Pastorino, F. et al. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res. 63, 7400–7409 (2003).

    CAS  PubMed  Google Scholar 

  126. Mauceri, H. J. et al. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394, 287–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Wachsberger, P., Burd, R. & Dicker, A. P. Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin. Cancer Res. 9, 1957–1971 (2003).

    CAS  PubMed  Google Scholar 

  128. Kaban, L. B. et al. Antiangiogenic therapy of a recurrent giant cell tumor of the mandible with interferon α-2a. Pediatrics 103, 1145–1149 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Ezekowitz, R. A., Mulliken, J. B. & Folkman, J. Interferon α-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Med. 326, 1456–1463 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Slaton, J. W., Perrotte, P., Inoue, K., Dinney, C. P. & Fidler, I. J. Interferon-α-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin. Cancer Res. 5, 2726–2734 (1999).

    CAS  PubMed  Google Scholar 

  131. Eisenhauer, E. A. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. The Michel Clavel Lecture. Ann. Oncol. 9, 1047–1052 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Cristofanilli, M., Charnsangavej, C. & Hortobagyi, G. N. Angiogenesis modulation in cancer research: novel clinical approaches. Nature Rev. Drug Discov. 1, 415–426 (2002).

    Article  CAS  Google Scholar 

  133. Wolf, W., Presant, C. A., Waluch, V. & Le Berthon, B. J. Response to anticancer treatment with Docetaxel (DOC) administered every 3 weeks (Q3w) and weekly (Q1w) is associated with functional assessment of changes in tumoral blood flow/perfusion. Proc. Am. Assoc. Cancer Res. A5343 (2003).

  134. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955–3964 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Rabascio, C. et al. Assessing tumour angiogenesis: increased circulating VE-cadherin RNA in patients with cancer indicates viability of circulating endothelial cells. Cancer Res. (in the press).

  136. Su, Y. B. et al. Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications. J. Clin. Oncol. 22, 610–616 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Kaur, H. & Budd, G. T. Metronomic therapy for breast cancer. Curr. Oncol. Rep. 6, 49–52 (2004).

    Article  PubMed  Google Scholar 

  138. Kieran, M. W. Anti-angiogenic chemotherapy in central nervous system tumors. Cancer Treat. Res. 117, 337–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Gluck, S. et al. Metronomic therapy in recurrent and metastatic chemo-resistant SCCHN: Data from a pilot study. Proc. Am. Soc. Clin. Oncol. 22, A2066 (2003).

    Google Scholar 

  140. Buckstein, R. et al. High dose celecoxib and low dose cyclophosphamide for relapsed aggressive histology NHL. Proc. Am. Soc. Clin. Oncol. 22, A827 (2003).

    Google Scholar 

  141. Bjarnason, G. A. et al. Phase II trial of continuous low dose cyclophosphamide and celecoxib in patients with progressing advanced renal cell carcinoma (RCC). Proc. Am. Soc. Clin. Oncol. 22, A1717 (2003).

    Google Scholar 

  142. Bergers, G. & Hanahan, D. Combining antiangiogenic agents with metronimoic chemotherapy enhances efficacy against late-stage pancreatic islet carcinomas in mice. Cold Spring Harb. Symp. Quant. Biol. 67, 293–300.

Download references

Acknowledgements

We are grateful to C. Cheng for her excellent secretarial and editorial assistance. We thank U. Emmenegger for critical reading of the manuscript. R.S.K. is a Canada Research Chair in Molecular Medicine whose research is supported by grants from the National Institutes of Health (USA), the National Cancer Institute of Canada, and the Canadian Institutes of Health Research. B.A.K. is an Amercian Cancer Society Clinical Research professor. This review is dedicated to T. Browder, whose pioneering studies in the laboratory of J. Folkman opened up the area of anti-angiogenic metronomic chemotherapy.

Author information

Authors and Affiliations

  1. Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, M4N 3M5, Ontario, Canada

    Robert S. Kerbel

  2. Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, 08901, NJ, USA

    Barton A. Kamen

Authors
  1. Robert S. Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barton A. Kamen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert S. Kerbel.

Ethics declarations

Competing interests

R.S. Kerbel is a consultant and recipient of a sponsored research agreement with ImClone Systems, New York, and Taiho Pharmaceuticals, Japan.

Related links

Related links

DATABASES

Cancer.gov

acute lymphoblastic leukaemia

breast cancer

colorectal cancer

melanoma

neuroblastoma

non-Hodgkin's lymphoma

non-small-cell lung cancer

ovarian cancer

prostate cancer

rhabdomyosarcoma

Entrez Gene

angiopoietin 1

bFGF

CD36

COX2

ERBB2

G-CSF

IFN-α

MDR1

TSP1

VE-cadherin

VEGF

VEGFR2

OMIM

Wilms' tumour

FURTHER INFORMATION

Angiogenesis Foundation

Glossary

METRONOMIC CHEMOTHERAPY

Chronic administration of chemotherapy at relatively low, non-toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks.

MATRIGEL-PERFUSION ASSAY OF ANGIOGENESIS

An assay that is widely used to measure angiogenesis. In this assay, an extracellular matrix gel-like plug (Matrigel) that contains angiogenic factors is implanted into the skin of mice. The new blood vessels that grow into the plug can be quantified by measuring perfusion of haemoglobin or large fluorescently tagged molecules (such as intravenously admininstered dextran) into the plugs.

CORNEAL-MICROPOCKET ANGIOGENESIS ASSAY

An assay for angiogenesis in which an inert polymer that contains an angiogenic growth factor, such as bFGF or VEGF, is implanted into the avascular cornea of mice or rabbits. This induces new blood vessels that can be visualized and quantified.

ADJUVANT THERAPY

Administration of certain anticancer drugs, such as tamoxifen, for prolonged periods — even as long as 3–5 years. This form of treatment is usually used to treat microscopic metastatic disease, after surgical removal of the primary tumour, or sometimes for treatments of a primary tumour, in which case it is called neoadjuvant therapy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kerbel, R., Kamen, B. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4, 423–436 (2004). https://doi.org/10.1038/nrc1369

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1369

This article is cited by

Search

Advanced 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