PMID- 19764996
OWN - NLM
STAT- MEDLINE
DCOM- 20100318
LR  - 20211203
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Linking)
VI  - 100
IP  - 12
DP  - 2009 Dec
TI  - Synergistic antiproliferative effect of mTOR inhibitors in combination with 
      5-fluorouracil in scirrhous gastric cancer.
PG  - 2402-10
LID - 10.1111/j.1349-7006.2009.01315.x [doi]
AB  - The aim of this study is to clarify the benefit of combination chemotherapy in 
      gastric cancer based on a cell-signal inhibitor and an anticancer drug. Two 
      scirrhous gastric cancer cell lines and two non-scirrhous gastric cancer cell 
      lines were used. Five anticancer drugs (5-fluorouracil [5FU], paclitaxel, 
      oxaliplatin, irinotecan, and gemcitabine) and four cell-signal inhibitors, 
      mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3beta, 
      p38alphabetaMAPK, and cyclin-dependent kinase, were used. The proliferation of 
      cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer 
      cells and the expression of apoptosis-related molecules were examined by flow 
      cytometry, real-time PCR, and immunostaining. mTOR inhibitors with 5FU showed a 
      synergistic antiproliferative effect in scirrhous gastric cancer, whereas the 
      other signal inhibitors showed no synergistic effect with any anticancer drugs. 
      mTOR inhibitor decreased the IC(50) of 5FU and increased the apoptosis rate in 
      scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. 
      The pan-caspase inhibitor, zVAD-fmk, inhibits apoptosis induced in combination 
      with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine 
      dehydrogenase, thymidylatesynthase, and bcl-2 expression, and increased caspase-3 
      and p21 expression of scirrhous gastric cancer cells, but did not affect those of 
      non-scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor 
      significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These 
      findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner 
      in scirrhous gastric cancer cells by the activation of the apoptosis signal. 
      Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 
      5FU in scirrhous gastric cancer.
FAU - Matsuzaki, Taro
AU  - Matsuzaki T
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Abeno-ku, Osaka, Japan.
FAU - Yashiro, Masakazu
AU  - Yashiro M
FAU - Kaizaki, Ryoji
AU  - Kaizaki R
FAU - Yasuda, Koichi
AU  - Yasuda K
FAU - Doi, Yosuke
AU  - Doi Y
FAU - Sawada, Tetsuji
AU  - Sawada T
FAU - Ohira, Masaichi
AU  - Ohira M
FAU - Hirakawa, Kosei
AU  - Hirakawa K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090818
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adenocarcinoma, Scirrhous/*drug therapy/pathology
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Synergism
MH  - Fluorouracil/*administration & dosage
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Stomach Neoplasms/*drug therapy/pathology
MH  - TOR Serine-Threonine Kinases
MH  - Xenograft Model Antitumor Assays
EDAT- 2009/09/22 06:00
MHDA- 2010/03/20 06:00
CRDT- 2009/09/22 06:00
PHST- 2009/09/22 06:00 [entrez]
PHST- 2009/09/22 06:00 [pubmed]
PHST- 2010/03/20 06:00 [medline]
AID - CAS1315 [pii]
AID - 10.1111/j.1349-7006.2009.01315.x [doi]
PST - ppublish
SO  - Cancer Sci. 2009 Dec;100(12):2402-10. doi: 10.1111/j.1349-7006.2009.01315.x. Epub 
      2009 Aug 18.