Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells

  • Authors:
    • T Takechi
    • J Uchida
    • A Fujioka
    • M Fukushima
  • View Affiliations

  • Published online on: November 1, 1997     https://doi.org/10.3892/ijo.11.5.1041
  • Pages: 1041-1044
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Abstract

We analyzed dihydropyrimidine dehydrogenase (DPD) activity (radioenzymatic assay) and 5-fluorouracil (5-FU) cytotoxicity (MTT test) in the absence or presence of uracil in two human cancer cell lines, MIAPaCa-2 (pancreas tumor) and HuTu80 (duodenum tumor). Basal DPD activities in both were comparatively high; MIAPaCa-2, 101 and HuTu80, 153 pmol/min/mg protein, respectively. Twenty mu g/ml of uracil, a dose which did not influence cell proliferation, enhanced 5-FU cytotoxicity; MIAPaCa-2, 2.0-fold and HuTu80, 1.5-fold, respectively. Uracil inhibited both DPD activity and cell growth in a concentration-dependent manner, and exhibited maximum effect at molar ratios to 5-FU of more than 10 (DPD activity, almost complete inhibition; growth-inhibitory effect, about a 30% increase). In addition, the cytosolic DPD activity of OCC-1 human head and neck tumors, collected following the oral administration of ss mg/kg of uracil to tumor-bearing nude mice, decreased to about 50% of that of OCC-1 tumors not treated with uracil. These findings suggested that combined fluoropyrimidine and uracil treatment of tumors with high basal DPD, elicits a greater antitumor effect than fluoropyrimidines alone, since uracil could inhibit the degradation of 5-FU in the tumor. UFT, an oral fluoropyrimidine combined with uracil, is expected to be more effective in such tumors.

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November 1997
Volume 11 Issue 5

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

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Spandidos Publications style
Takechi T, Uchida J, Fujioka A and Fukushima M: Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells. Int J Oncol 11: 1041-1044, 1997.
APA
Takechi, T., Uchida, J., Fujioka, A., & Fukushima, M. (1997). Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells. International Journal of Oncology, 11, 1041-1044. https://doi.org/10.3892/ijo.11.5.1041
MLA
Takechi, T., Uchida, J., Fujioka, A., Fukushima, M."Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells". International Journal of Oncology 11.5 (1997): 1041-1044.
Chicago
Takechi, T., Uchida, J., Fujioka, A., Fukushima, M."Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells". International Journal of Oncology 11, no. 5 (1997): 1041-1044. https://doi.org/10.3892/ijo.11.5.1041