RRC ID 42599
Author Miyazaki K, Shibahara T, Sato D, Uchida K, Suzuki H, Matsui H, Yanaka A, Nakahara A, Matsuzaki Y.
Title Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines.
Journal J Gastroenterol
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.
Volume 41(2)
Pages 140-50
Published 2006-2-1
DOI 10.1007/s00535-005-1733-6
PMID 16568373
MeSH Antimetabolites, Antineoplastic / pharmacology* Apoptosis Caco-2 Cells Camptothecin / pharmacology Cell Line, Tumor Cisplatin / pharmacology Colonic Neoplasms / enzymology* Cytokines / pharmacology* Dihydrouracil Dehydrogenase (NADP) / metabolism Fluorouracil / metabolism* Fluorouracil / pharmacology* HT29 Cells Humans Interferons / pharmacology Ligands Mitomycin / pharmacology Orotate Phosphoribosyltransferase / metabolism Paclitaxel / pharmacology RNA, Messenger / analysis Thymidine Phosphorylase / metabolism Thymidylate Synthase / metabolism
IF 6.132
Times Cited 23
Human and Animal Cells CACO-2(RCB0988)