Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide

  • Authors:
    • Yasuhide Motoyoshi
    • Kazuhisa Kaminoda
    • Ohki Saitoh
    • Keisuke Hamasaki
    • Kazuhiko Nakao
    • Nobuko Ishii
    • Yuji Nagayama
    • Katsumi Eguchi
  • View Affiliations

  • Published online on: July 1, 2006     https://doi.org/10.3892/or.16.1.141
  • Pages: 141-146
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Abstract

It is known that, besides its direct cytotoxic effect as an alkylating chemotherapeutic agent, cyclophosphamide also has immuno-modulatory effects, such as depletion of CD4+CD25+ regulatory T cells. However, its optimal concentration has not yet been fully elucidated. Therefore, we first compared the effects of different doses of cyclophosphamide on T cell subsets including CD4+CD25+ T cells in mice. Cyclophosphamide (20 mg/kg) decreased the numbers of splenocytes, CD4+ and CD8+ T cells by ≈50%, while a decline in CD4+CD25+ T cell number was more profound, leading to the remarkably lower ratios of CD4+CD25+ T cells to CD4+ T cells. In contrast, 200 mg/kg cyclophosphamide severely decreased the numbers of all the T cell subsets by >90% although the decreased ratios of CD4+CD25+ T cells to CD4+ T cells were still observed. Next, low-dose cyclophosphamide significantly inhibited in vivo growth of murine hepatoma MH129 tumor in immuno-competent but not immuno-deficient mice. This anti-tumor effect was abolished by CD4+CD25+ T cell repletion. In contrast, high-dose cyclophosphamide exhibited similar anti-tumor effects in both mice. In addition, contrary to antibody-mediated CD4+CD25+ T cell depletion, administration of low-dose cyclophosphamide after tumor inoculation was more efficacious than the prior administration. Our data show that low-dose cyclophosphamide selectively depletes CD4+CD25+ T cells, leading to enhanced anti-tumor effects against pre-existing tumors, while the anti-tumor effect of high-dose cyclophosphamide is solely attributed to its direct cytotoxicity. These findings appear to be highly crucial in a clinical setting of combined chemotherapy and immunotherapy for cancer treatment.

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July 2006
Volume 16 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Motoyoshi Y, Kaminoda K, Saitoh O, Hamasaki K, Nakao K, Ishii N, Nagayama Y and Eguchi K: Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol Rep 16: 141-146, 2006
APA
Motoyoshi, Y., Kaminoda, K., Saitoh, O., Hamasaki, K., Nakao, K., Ishii, N. ... Eguchi, K. (2006). Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncology Reports, 16, 141-146. https://doi.org/10.3892/or.16.1.141
MLA
Motoyoshi, Y., Kaminoda, K., Saitoh, O., Hamasaki, K., Nakao, K., Ishii, N., Nagayama, Y., Eguchi, K."Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide". Oncology Reports 16.1 (2006): 141-146.
Chicago
Motoyoshi, Y., Kaminoda, K., Saitoh, O., Hamasaki, K., Nakao, K., Ishii, N., Nagayama, Y., Eguchi, K."Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide". Oncology Reports 16, no. 1 (2006): 141-146. https://doi.org/10.3892/or.16.1.141