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Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines

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Abstract

Background

Several studies have demonstrated that intratumoral expression of catabolizing and anabolizing enzymes for 5-fluorouracil (5-FU) is important in the response of cancers to 5-FU-based chemotherapy. We investigated the influence of other chemotherapeutic agents or cytokines, which are often administered for enhancing the efficacy of 5-FU, on the tumoral expression of 5-FU-associated enzymes, i.e., dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), orotate phosphoribosyl transferase (OPRT), and thymidine phosphorylase (TP).

Methods

Human colon cancer cell lines (HT-29, Caco-2, and DLD-1) were incubated with 5-FU and with 5-FU combined with cisplatin, camptothecin, paclitaxel, mitomycin C, interferon, or TNF-related apoptosis-inducing ligand. mRNA expression of 5-FU-associated enzymes was assessed by real-time PCR. Activity of each enzyme and intracellular 5-FU accumulation after incubation with such agents were also evaluated.

Results

Each agent had a synergistic effect on the cytotoxicity of 5-FU. All chemotherapeutic agents other than cytokines induced marked alteration of the mRNA expression profile of 5-FU-associated enzymes; depression of DPD, elevation of TS, and slight suppression of OPRT and TP. In accordance with mRNA expression, enzyme activity of DPD was significantly depressed by such agents. Furthermore, although 5-FU itself increased DPD mRNA expression, a mechanism considered to be related to the acquisition of 5-FU resistance, the addition of cisplatin or camptothecin significantly inhibited the 5-FU-induced elevation of DPD.

Conclusions

5-FU-associated enzymes in colon cancer cells were greatly influenced by various chemotherapeutic agents; in particular, DPD expression was depressed. These results appear important in planning chemotherapy and also in understanding the development of adverse effects of 5-FU.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Comprehensive Human Science, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, 305-8575, Japan

    Kaori Miyazaki, Takeshi Shibahara, Daisuke Sato, Hideo Suzuki, Hirofumi Matsui, Akinori Yanaka, Akira Nakahara & Yasushi Matsuzaki

  2. Department of Molecular Biology and Molecular Oncology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan

    Kazuhiko Uchida

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  1. Kaori Miyazaki
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Miyazaki, K., Shibahara, T., Sato, D. et al. Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines. J Gastroenterol 41, 140–150 (2006). https://doi.org/10.1007/s00535-005-1733-6

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