Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.

  • Authors:
    • Y Murakami
    • H Kazuno
    • T Emura
    • H Tsujimoto
    • N Suzuki
    • M Fukushima
  • View Affiliations

  • Published online on: August 1, 2000     https://doi.org/10.3892/ijo.17.2.277
  • Pages: 277-360
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Abstract

5-Fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FdUrd) and 5-trifluorothymidine (F3(d)Thd) are antimetabolites which are metabolized to their corresponding active forms which inhibit DNA synthesis via inhibition of thymidylate synthase (TS). To investigate ways of overcoming 5-FU-resistance, we established acquired-resistant colorectal cancer cell lines against these three drugs by continuous and step-wise escalation of drugs, and analyzed the cytotoxicity and the mechanism of resistance to the drugs. When cells were incubated with the 3 drugs for 72 h, the resistance ratio to parental DLD-1 human colorectal tumor cells was 65.2 for DLD-1/5-FU, 9.7 for DLD-1/FdUrd and 448.6 for DLD-1/F3(d)Thd cells. DLD-1/5-FU cells did not show any cross-resistance against FdUrd and F(3)dThd. However, DLD-1/FdUrd cells showed 3- and 9-fold increased resistance to 5-FU and F3(d)Thd, respectively, and DLD-1/F3(d)Thd cells also showed about 90-fold resistance to FdUrd. Analysis of enzyme activities and gene expression associated with pyrimidine metabolism indicated that a significant decrease in orotate phosphoribosyltransferase activity in DLD-1/5-FU cells, a 7-fold increase of TS mRNA in DLD-1/FdUrd cells, and a 37-fold decrease in thymidine kinase activity of DLD-1/F3(d)Thd cells were the major mechanisms of drug resistance. These findings were closely associated with the cytotoxicity of 5-FU, FdUrd and F3(d)Thd against the established 5-FU-, FdUrd- or F3(d)Thd-resistant cells. When DLD-1/FdUrd cells expressing increased TS mRNA were treated with FdUrd and F3(d)Thd for only 4 h, the resistance ratios of DLD-1/FdUrd cells to parental DLD-1 cells were markedly different for FdUrd and F3(d)Thd, suggesting that the cytotoxicity with short-time exposure to F3(d)Thd is due to a mechanism other than TS inhibition, although the cytotoxicity of F3(d)Thd in the short-time is low compared to that of long-time exposure. In conclusion, F3(d)Thd, an antimetabolite that inhibits TS activity, may be effective against 5-FU and/or FdUrd-resistance in colorectal cancer cells caused by amplification of TS and/or deletion of orotate phosphoribosyltransferase.

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Aug 2000
Volume 17 Issue 2

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

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Spandidos Publications style
Murakami Y, Kazuno H, Emura T, Tsujimoto H, Suzuki N and Fukushima M: Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.. Int J Oncol 17: 277-360, 2000.
APA
Murakami, Y., Kazuno, H., Emura, T., Tsujimoto, H., Suzuki, N., & Fukushima, M. (2000). Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.. International Journal of Oncology, 17, 277-360. https://doi.org/10.3892/ijo.17.2.277
MLA
Murakami, Y., Kazuno, H., Emura, T., Tsujimoto, H., Suzuki, N., Fukushima, M."Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.". International Journal of Oncology 17.2 (2000): 277-360.
Chicago
Murakami, Y., Kazuno, H., Emura, T., Tsujimoto, H., Suzuki, N., Fukushima, M."Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.". International Journal of Oncology 17, no. 2 (2000): 277-360. https://doi.org/10.3892/ijo.17.2.277