Combination therapy of interferon-α and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins

  • Authors:
    • Hiroshi Wada
    • Hiroaki Nagano
    • Hirofumi Yamamoto
    • Isao Arai
    • Hideo Ota
    • Masato Nakamura
    • Bazarragchaa Damdinsuren
    • Takehiro Noda
    • Shigeru Marubashi
    • Atsushi Miyamoto
    • Yutaka Takeda
    • Koji Umeshita
    • Yuichiro Doki
    • Keizo Dono
    • Shoji Nakamori
    • Masato Sakon
    • Morito Monden
  • View Affiliations

  • Published online on: October 1, 2007     https://doi.org/10.3892/or.18.4.801
  • Pages: 801-809
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Abstract

We recently reported that interferon-α (IFN-α) and 5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC) achieved excellent clinical results. However, the mechanism underlying this combination therapy remains to be elucidated. In this study, we examined the anti-tumor effects of IFN-α and 5-FU combination therapy in vivo and aimed to reveal its anti-angiogenic effects by investigating the expression of vascular endothelial growth factor (VEGF) and angiopoietins (Ang-1 and Ang-2). Human HCC cells, HuH7, were subcutaneously injected in nude mice. Ten days later, groups of mice received treatment with IFN-α alone, 5-FU alone, or with a combination of IFN-α and 5-FU for four weeks. Immunohistochemical examinations of proliferating cell nuclear antigen (PCNA), cell differentiation antigen 34 (CD34), Ang-1, -2 and VEGF, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and quantification of VEGF, Ang-1 and-2 mRNA using real-time RT-PCR were performed. Results showed that IFN-α and 5-FU combination therapy significantly inhibited the growth of human HCC cells compared with the control group or single agent treatment. The combination therapy decreased PCNA-positive cells as well as microvessel density (MVD) and induced apoptosis of (TUNEL-positive cells) more than other treatment groups. Immunohistochemical analysis revealed that the combination therapy significantly decreased the expression of VEGF and Ang-2 and increased that of Ang-1. The ANG2/ANG1 mRNA expression ratio was significantly lower in the combination therapy group. In conclusion, our results suggested that IFN-α and 5-FU combination therapy has anti-proliferative and anti-angiogenic effects and can induce apoptosis in vivo. The synergistic and anti-angiogenic effects may in part be attributable to the regulation of Ang-1, -2 and VEGF.

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October 2007
Volume 18 Issue 4

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

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Spandidos Publications style
Wada H, Nagano H, Yamamoto H, Arai I, Ota H, Nakamura M, Damdinsuren B, Noda T, Marubashi S, Miyamoto A, Miyamoto A, et al: Combination therapy of interferon-α and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncol Rep 18: 801-809, 2007
APA
Wada, H., Nagano, H., Yamamoto, H., Arai, I., Ota, H., Nakamura, M. ... Monden, M. (2007). Combination therapy of interferon-α and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncology Reports, 18, 801-809. https://doi.org/10.3892/or.18.4.801
MLA
Wada, H., Nagano, H., Yamamoto, H., Arai, I., Ota, H., Nakamura, M., Damdinsuren, B., Noda, T., Marubashi, S., Miyamoto, A., Takeda, Y., Umeshita, K., Doki, Y., Dono, K., Nakamori, S., Sakon, M., Monden, M."Combination therapy of interferon-α and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins". Oncology Reports 18.4 (2007): 801-809.
Chicago
Wada, H., Nagano, H., Yamamoto, H., Arai, I., Ota, H., Nakamura, M., Damdinsuren, B., Noda, T., Marubashi, S., Miyamoto, A., Takeda, Y., Umeshita, K., Doki, Y., Dono, K., Nakamori, S., Sakon, M., Monden, M."Combination therapy of interferon-α and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins". Oncology Reports 18, no. 4 (2007): 801-809. https://doi.org/10.3892/or.18.4.801