PMID- 15578690
OWN - NLM
STAT- MEDLINE
DCOM- 20050519
LR  - 20211203
IS  - 1045-2257 (Print)
IS  - 1045-2257 (Linking)
VI  - 42
IP  - 3
DP  - 2005 Mar
TI  - Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis 
      mouse models.
PG  - 213-27
AB  - Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is 
      no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene 
      lead to increased mammalian target of rapamycin (mTOR) kinase activity in the 
      conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, 
      and protein translation. The normal function of TSC1 and TSC2 gene products is to 
      form a complex that reduces mTOR kinase activity. Thus, mTOR kinase inhibition 
      may be a useful targeted therapeutic approach. Elevated interferon-gamma 
      (IFN-gamma) expression is associated with decreased severity of kidney tumors in 
      TSC patients and mouse models; therefore, IFN-gamma also has therapeutic 
      potential. We studied cohorts of Tsc2+/- mice and a novel mouse model of 
      Tsc2-null tumors in order to evaluate the efficacy of targeted therapy for TSC. 
      We found that treatment with either an mTOR kinase inhibitor (CCI-779, a 
      rapamycin analog) or with IFN-gamma reduced the severity of TSC-related disease 
      without significant toxicity. These results constitute definitive preclinical 
      data that justify proceeding with clinical trials using these agents in selected 
      patients with TSC and related disorders.
FAU - Lee, Laifong
AU  - Lee L
AD  - Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Sudentas, Paul
AU  - Sudentas P
FAU - Donohue, Brian
AU  - Donohue B
FAU - Asrican, Kirsten
AU  - Asrican K
FAU - Worku, Aelaf
AU  - Worku A
FAU - Walker, Victoria
AU  - Walker V
FAU - Sun, Yanping
AU  - Sun Y
FAU - Schmidt, Karl
AU  - Schmidt K
FAU - Albert, Mitchell S
AU  - Albert MS
FAU - El-Hashemite, Nisreen
AU  - El-Hashemite N
FAU - Lader, Alan S
AU  - Lader AS
FAU - Onda, Hiroaki
AU  - Onda H
FAU - Zhang, Hongbing
AU  - Zhang H
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
FAU - Dabora, Sandra L
AU  - Dabora SL
LA  - eng
GR  - CA086248/CA/NCI NIH HHS/United States
GR  - DK066366/DK/NIDDK NIH HHS/United States
GR  - HL007680/HL/NHLBI NIH HHS/United States
GR  - NS31535/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Genes Chromosomes Cancer
JT  - Genes, chromosomes & cancer
JID - 9007329
RN  - 0 (Repressor Proteins)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 624KN6GM2T (temsirolimus)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cystadenoma/metabolism/pathology/prevention & control
MH  - *Disease Models, Animal
MH  - Drug Therapy, Combination
MH  - Hemangioma/metabolism/pathology/prevention & control
MH  - Interferon-gamma/*therapeutic use
MH  - Kidney Neoplasms/metabolism/pathology/prevention & control
MH  - Liver Neoplasms, Experimental/metabolism/pathology/prevention & control
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Nude
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Repressor Proteins/genetics/*physiology
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*analogs & derivatives/*therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis/*drug therapy/metabolism/pathology
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/*physiology
EDAT- 2004/12/04 09:00
MHDA- 2005/05/20 09:00
CRDT- 2004/12/04 09:00
PHST- 2004/12/04 09:00 [pubmed]
PHST- 2005/05/20 09:00 [medline]
PHST- 2004/12/04 09:00 [entrez]
AID - 10.1002/gcc.20118 [doi]
PST - ppublish
SO  - Genes Chromosomes Cancer. 2005 Mar;42(3):213-27. doi: 10.1002/gcc.20118.