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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.

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

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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.

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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

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Correspondence to Robert S. Kerbel.

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

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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.

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

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