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Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase

Academic Article
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Overview

authors

  • Loeffler, M.
  • Kruger, J. A.
  • Reisfeld, Ralph

publication date

  • June 2005

journal

  • Cancer Research  Journal

abstract

  • Cyclophosphamide is a widely used chemotherapeutic drug that was recently applied as either an antiangiogenic/antivasculogenic or an immunostimulatory agent in combination with cancer immunotherapies. It has been previously shown that cyclophosphamide augments the efficacy of antitumor immune responses by depleting CD4+ CD25+ T regulatory cells and increasing both T-lymphocyte proliferation and T memory cells. Furthermore, cyclophosphamide was shown to mediate killing of circulating endothelial progenitors. However, the molecular basis for these observations has not yet been elucidated. We show here that the cyclophosphamide-mediated inhibition of inducible nitric oxide synthase is directly linked to its immunostimulatory but not to its antivasculogenic effects. Moreover, combined application of cyclophosphamide with a novel, oral DNA vaccine targeting platelet-derived growth factor B (PDGF-B), overexpressed by proliferating endothelial cells in the tumor vasculature, not only completely inhibited the growth of different tumor types but also led to tumor rejections in mice. These findings provide a new rationale at the molecular level for the combination of chemotherapy and immunotherapy in cancer treatment.

subject areas

  • Adjuvants, Immunologic
  • Animals
  • Cancer Vaccines
  • Carcinoma, Lewis Lung
  • Cyclophosphamide
  • Dose-Response Relationship, Immunologic
  • Drug Synergism
  • Female
  • Lymphoid Tissue
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Plasmacytoma
  • Proto-Oncogene Proteins c-sis
  • Salmonella Vaccines
  • Salmonella typhimurium
  • Vaccines, Attenuated
  • Vaccines, DNA
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Identity

International Standard Serial Number (ISSN)

  • 0008-5472

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.can-05-0646

PubMed ID

  • 15958544
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Additional Document Info

start page

  • 5027

end page

  • 5030

volume

  • 65

issue

  • 12

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