PMID- 17318075
OWN - NLM
STAT- MEDLINE
DCOM- 20070326
LR  - 20211203
IS  - 0041-1337 (Print)
IS  - 0041-1337 (Linking)
VI  - 83
IP  - 4
DP  - 2007 Feb 27
TI  - Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of 
      patients undergoing liver transplantation.
PG  - 425-32
AB  - BACKGROUND: Because mammalian target of rapamycin (mTOR) inhibitors combine 
      anticancer and immunosuppressive properties we investigated: 1) the activation 
      status and prognostic significance of the mTOR pathway in hepatocellular 
      carcinoma (HCC) tissues of patients undergoing orthotopic liver transplantation 
      (OLT) for HCC, and 2) the single and combinatorial efficacy of RAD001 in HCC 
      cells. METHODS: PTEN, p-AKT, p-mTOR, p-p70S6K, and p-4EBP-1 were analyzed by 
      immunohistochemistry in explanted HCCs of 166 patients undergoing OLT. Efficacy 
      of RAD001 as mono- and combination therapy with doxorubicin was tested in Hep3B 
      and SNU398 cells. RESULTS: The mTOR pathway is activated in about 40% of patients 
      undergoing OLT for HCC but no direct correlation between up- and downstream 
      proteins was observed. We found no influence of mTOR pathway protein expression 
      on disease free survival (DFS) or overall survival (OS). There was a marked 
      single agent and chemo-sensitizing effect of RAD001 against HCC cells in vitro. 
      CONCLUSION: The mTOR pathway is active in 40% of patients with HCC undergoing 
      OLT, but has no influence of DFS or OS. No direct correlation was observed 
      between up- and downstream proteins limiting the use of upstream proteins to 
      predict mTOR activity. Prospective clinical trials are needed to test whether the 
      activation status of the mTOR pathway in HCCs predicts the antitumor effect of 
      rapamycin derivative in the posttransplantation course.
FAU - Sieghart, Wolfgang
AU  - Sieghart W
AD  - Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular 
      Pharmacology, Medical University Vienna, Vienna, Austria.
FAU - Fuereder, Thorsten
AU  - Fuereder T
FAU - Schmid, Katharina
AU  - Schmid K
FAU - Cejka, Daniel
AU  - Cejka D
FAU - Werzowa, Johannes
AU  - Werzowa J
FAU - Wrba, Fritz
AU  - Wrba F
FAU - Wang, Xiaowei
AU  - Wang X
FAU - Gruber, Diego
AU  - Gruber D
FAU - Rasoul-Rockenschaub, Susanne
AU  - Rasoul-Rockenschaub S
FAU - Peck-Radosavljevic, Markus
AU  - Peck-Radosavljevic M
FAU - Wacheck, Volker
AU  - Wacheck V
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Carcinoma, Hepatocellular/*metabolism/pathology/surgery
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Disease-Free Survival
MH  - Doxorubicin/pharmacology
MH  - Drug Therapy, Combination
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - *Liver Transplantation
MH  - Male
MH  - Middle Aged
MH  - Protein Kinases/*metabolism
MH  - Signal Transduction
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/02/24 09:00
MHDA- 2007/03/27 09:00
CRDT- 2007/02/24 09:00
PHST- 2007/02/24 09:00 [pubmed]
PHST- 2007/03/27 09:00 [medline]
PHST- 2007/02/24 09:00 [entrez]
AID - 00007890-200702270-00010 [pii]
AID - 10.1097/01.tp.0000252780.42104.95 [doi]
PST - ppublish
SO  - Transplantation. 2007 Feb 27;83(4):425-32. doi: 
      10.1097/01.tp.0000252780.42104.95.