Document Detail

Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines.
MedLine Citation:
PMID:  16557585     Owner:  NLM     Status:  MEDLINE    
We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors.
Yoshiyuki Wada; Kazuhiro Yoshida; Takahisa Suzuki; Hirozumi Mizuiri; Kazuo Konishi; Kei Ukon; Kazuaki Tanabe; Yu Sakata; Masakazu Fukushima
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  119     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-06-08     Completed Date:  2006-08-09     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  783-91     Citation Subset:  IM    
Copyright Information:
Copyright 2006 Wiley-Liss, Inc.
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
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MeSH Terms
Cell Line, Tumor
Cell Proliferation / drug effects
Dihydrouracil Dehydrogenase (NADP) / metabolism
Drug Combinations
Drug Synergism
Fluorouracil / metabolism*
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Mice, Nude
Multienzyme Complexes / genetics,  metabolism
Orotate Phosphoribosyltransferase / genetics,  metabolism
Orotidine-5'-Phosphate Decarboxylase / genetics,  metabolism
Oxonic Acid / pharmacology*
Stomach Neoplasms / enzymology*,  pathology
Taxoids / pharmacology*
Tegafur / pharmacology*
Thymidylate Synthase / metabolism
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Drug Combinations; 0/Multienzyme Complexes; 0/Taxoids; 150863-82-4/S 1 (combination); 15H5577CQD/docetaxel; 17902-23-7/Tegafur; 51-21-8/Fluorouracil; 74870-74-9/uridine 5'-monophosphate synthase; 937-13-3/Oxonic Acid; EC Dehydrogenase (NADP); EC Synthase; EC Phosphoribosyltransferase; EC'-Phosphate Decarboxylase

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