Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites

  • Authors:
    • Masahiro Inoue
    • Mutsuko Mukai
    • Yukou Hamanaka
    • Masaharu Tatsuta
    • Masahiro Hiraoka
    • Shinae Kizaka-Kondoh
  • View Affiliations

  • Published online on: September 1, 2004     https://doi.org/10.3892/ijo.25.3.713
  • Pages: 713-720
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Abstract

Tumor hypoxia in a solid tumor mass has long been recognized as a cause of resistance to current cancer therapies, and has also been suggested to be a potent driving force towards malignancy. Recent progress in the understanding of the molecular mechanism of the tumor response to hypoxia has increased attention on targeting hypoxia for cancer therapy. We have generated a hypoxia-targeting fusion protein, TOP3, which is composed of a protein transduction domain (PTD) of HIV TAT, an oxygen-dependent degradation domain (ODD) of HIF-1α, and procaspase-3. Here, we examine the effects of TOP3 in a rat ascites model. First, we clarified that the fluid in ascites from MM1 cells, which are derivatives of AH130 rat ascites hepatoma cells, was highly hypoxic. In vitro, MM1 cells retained protein degradation machinery through the ODD domain, and TOP3 effectively impaired MM1 cell growth in culture under hypoxic conditions by inducing apoptosis. Intraperitoneal administration of TOP3 prolonged the life span of rats bearing a significant amount of malignant ascites, and 60% of the treated animals were cured without recurrence of ascites. Thus, TOP3 had a dramatic effect on malignant ascites and, hence, we propose that rodent malignant ascites is an appropriate platform for testing hypoxia-targeted drugs.

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September 2004
Volume 25 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Inoue M, Mukai M, Hamanaka Y, Tatsuta M, Hiraoka M and Kizaka-Kondoh S: Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites. Int J Oncol 25: 713-720, 2004
APA
Inoue, M., Mukai, M., Hamanaka, Y., Tatsuta, M., Hiraoka, M., & Kizaka-Kondoh, S. (2004). Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites. International Journal of Oncology, 25, 713-720. https://doi.org/10.3892/ijo.25.3.713
MLA
Inoue, M., Mukai, M., Hamanaka, Y., Tatsuta, M., Hiraoka, M., Kizaka-Kondoh, S."Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites". International Journal of Oncology 25.3 (2004): 713-720.
Chicago
Inoue, M., Mukai, M., Hamanaka, Y., Tatsuta, M., Hiraoka, M., Kizaka-Kondoh, S."Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites". International Journal of Oncology 25, no. 3 (2004): 713-720. https://doi.org/10.3892/ijo.25.3.713