Document Detail


Mechanism of 5-fluorouracil required resistance in human hepatocellular carcinoma cell line Bel(7402).
MedLine Citation:
PMID:  12439919     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIM: To investigate the resistance mechanism of 5-fluorouracil (5-FU) in Bel(7402)/5-FU cells which was established in our lab by in vitro continuous stepwise exposure of human hepatocellular carcinoma (HCC) cell line Bel(7402) to 5-FU. METHODS: The expression of multidrug resistance-associated protein (MRP) and thymidylate synthase (TS) in Bel(7402) cells was detected by immonocytochemistry. The fluorescein (FLU) accumulation, an index of MRP functional activity, was determined by flow cytometry. The distribution of FLU was observed by confocal laser scanning microscope. The spectrofluorometry was used to show the intracelluar content of glutathione (GSH). Cell growth inhibition was determined by MTT assay. The activity of glutathione S-transferases (GSTs) was determined by spectrophotometry. RESULTS: A higher expression of MRP in the Bel(7402)/5-FU cells was observed by using monoclonal mouse anti-MRP antibody, MRPr-1, in comparison with Bel(7402) cells. Bel(7402)/5-FU cells also showed a significant decrease of FLU accumulation. FLU mainly accumulated in the nucleus with a high nuclear/cytoplasmic ratio in Bel(7402) cells, whereas there was no difference of FLU accumulation between the nucleus and cytoplasm in Bel(7402)/5-FU cells. The intracellular GSH content in Bel(7402)/5-FU cells was almost 3 folds higher than that in Bel(7402) cells. Addition of D, L-buthione-S, R-sulfoximine (BSO) dose-dependently reduced the GSH content in Bel(7402)/5-FU cells, however, only a weak enhancement on the cytotoxicity of 5-FU and doxorubicin (Dox) to Bel(7402)/5-FU cells was observed. Bel(7402)/5-FU cells also exhibited 29.1 % higher total GSTs activity than Bel(7402) cells. Immunocytochemical staining by using anti-TS monoclonal antibody TS 106 showed that the level of TS in Bel(7402)/5-FU cells elevated markedly as compared with Bel(7402) cells. CONCLUSION: The continuous exposure of Bel(7402) cells to 5-FU led to overexpression of TS and MRP, as well as increased intracellular GSH content and total GST activity.
Authors:
Jing Jin; Min Huang; Huai-Ling Wei; Geng-Tao Liu
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  World journal of gastroenterology : WJG     Volume:  8     ISSN:  1007-9327     ISO Abbreviation:  World J. Gastroenterol.     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-11-19     Completed Date:  2003-01-30     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  100883448     Medline TA:  World J Gastroenterol     Country:  China    
Other Details:
Languages:  eng     Pagination:  1029-34     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
Buthionine Sulfoximine / pharmacology
Carcinoma, Hepatocellular / drug therapy*,  metabolism
Drug Resistance, Neoplasm
Fluorescein / pharmacokinetics
Fluorouracil / pharmacology*
Glutathione / metabolism
Glutathione Transferase / metabolism
Humans
Liver Neoplasms / drug therapy*,  metabolism
Multidrug Resistance-Associated Proteins / metabolism
Thymidylate Synthase / metabolism
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Multidrug Resistance-Associated Proteins; 2321-07-5/Fluorescein; 5072-26-4/Buthionine Sulfoximine; 51-21-8/Fluorouracil; 70-18-8/Glutathione; EC 2.1.1.45/Thymidylate Synthase; EC 2.5.1.18/Glutathione Transferase

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