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Metronomic Low-Dose Antiangiogenic Chemotherapy in Mice and Man

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Antiangiogenic Agents in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Summary

Metronomic (antiangiogenic) chemotherapy refers to a form of dose dense chemotherapy involving close regular, even daily, administration of conventional chemotherapy drugs at relatively low doses over long periods in the absence of prolonged drug-free periods. Anti-tumor efficacy, which in some cases can be remarkably effective in various experimental mouse models of cancer, even in the absence of toxicity, is thought to be mediated mainly by antiangiogenic effects, either locally, by direct targeting of activated/dividing endothelial cells in the angiogenic tumor neovasculature, or systemically, by effects on circulating (bone marrow derived) endothelial progenitor cells (CEPs). However, additional mechanisms may also be involved, including stimulation of the immune system by targeting regulatory T cells, and possibly also direct effects on tumor cells—which could include the tumor stem cell(-like) subpopulation. Metronomic chemotherapy, because of its relatively nontoxic nature, is ideal for combination therapy using various targeted biologic agents, especially antiangiogenic drugs. Other promising combinatorial strategies include “doublet” metronomic chemotherapy using two different chemotherapy drugs, interspersing low-dose chemotherapy with higher bolus dose (BD) injections of the same drug, or short-course maximum tolerated dose (MTD) chemotherapy followed by long-term metronomic chemotherapy combined with a targeted biologic agent. Such combinations can sometimes have striking preclinical anti-tumor effects, even in models involving large primary tumors or widespread high-volume metastatic disease.

A number of clinical trials and pilot studies testing various combinatorial metronomic chemotherapy regimens have been undertaken which, in aggregate, appear to confirm encouraging clinical activity in certain advanced-stage cancers, with only modest or minimal host toxicity being observed. Larger randomized phase III trials are thus warranted, especially considering some of the potential advantages of metronomic chemotherapy. These include increased convenience when using oral chemotherapeutic drugs, reduced costs when off-patent chemotherapeutic drugs are used, and reduced severity of toxic side effects. These features make metronomic chemotherapy-type regimens ideal for adjuvant chemotherapy of early-stage cancers, an example of which is long-term, nontoxic daily oral tegafur-uracil (UFT) (a 5-FU prodrug composed of uracil and tegafur) for treatment of early-stage non-small cell lung cancer (NSCLC).

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Authors
  1. Robert S. Kerbel PhD
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  2. U. Emmenegger MD, PhD
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  3. S. Man BSc
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  4. R. Munoz PhD
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  5. C. Folkins BSc
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  6. Y. Shaked PhD
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Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

  2. M. D. Anderson Cancer Center, The University of Texas, Houston, TX

    Lee M. Ellis MD

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Kerbel, R.S., Emmenegger, U., Man, S., Munoz, R., Folkins, C., Shaked, Y. (2008). Metronomic Low-Dose Antiangiogenic Chemotherapy in Mice and Man. In: Teicher, B.A., Ellis, L.M. (eds) Antiangiogenic Agents in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-184-0_16

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  • DOI: https://doi.org/10.1007/978-1-59745-184-0_16

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-870-6

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