PMID- 14770419
OWN - NLM
STAT- MEDLINE
DCOM- 20040309
LR  - 20211203
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 100
IP  - 4
DP  - 2004 Feb 15
TI  - Mammalian target of rapamycin inhibition as therapy for hematologic malignancies.
PG  - 657-66
AB  - The mammalian target of rapamycin (mTOR) is a downstream effector of the 
      phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, 
      which mediates cell survival and proliferation. mTOR regulates essential 
      signal-transduction pathways, is involved in the coupling of growth stimuli with 
      cell cycle progression, and initiates mRNA translation in response to favorable 
      nutrient environments. mTOR is involved in regulating many aspects of cell 
      growth, including membrane traffic, protein degradation, protein kinase C 
      signaling, ribosome biogenesis, and transcription. Because mTOR activates both 
      the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 
      4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors 
      of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit 
      retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, 
      leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help 
      cause G1-phase arrest. It is known that the phosphatase and tensin homologue 
      tumor suppressor gene (PTEN) plays a major role in embryonic development, cell 
      migration, and apoptosis. Malignancies with PTEN mutations, which are associated 
      with constitutive activation of the PI3K/Akt pathway, are relatively resistant to 
      apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs 
      with relatively favorable pharmaceutical properties, including CCI-779, RAD001, 
      and AP23573, are under investigation in patients with hematologic malignancies.
CI  - Copyright 2004 American Cancer Society.
FAU - Panwalkar, Amit
AU  - Panwalkar A
AD  - Section of Developmental Therapeutics, Department of Leukemia, University of 
      Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
FAU - Verstovsek, Srdan
AU  - Verstovsek S
FAU - Giles, Francis J
AU  - Giles FJ
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 624KN6GM2T (temsirolimus)
RN  - 9HW64Q8G6G (Everolimus)
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)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cancer. 2004 Sep 15;101(6):1478; author reply 1478. PMID: 15368336
MH  - Apoptosis
MH  - Cell Division
MH  - Cell Survival
MH  - Cyclin-Dependent Kinases/pharmacology
MH  - Enzyme Activation/drug effects
MH  - Everolimus
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Genes, Tumor Suppressor
MH  - Germ-Line Mutation
MH  - Hematologic Neoplasms/*drug therapy
MH  - Humans
MH  - Immunosuppressive Agents/therapeutic use
MH  - PTEN Phosphohydrolase
MH  - Phosphoric Monoester Hydrolases/biosynthesis/pharmacology
MH  - Protein Kinases/pharmacology/*therapeutic use
MH  - Signal Transduction
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Proteins/biosynthesis/pharmacology
RF  - 116
EDAT- 2004/02/11 05:00
MHDA- 2004/03/10 05:00
CRDT- 2004/02/11 05:00
PHST- 2004/02/11 05:00 [pubmed]
PHST- 2004/03/10 05:00 [medline]
PHST- 2004/02/11 05:00 [entrez]
AID - 10.1002/cncr.20026 [doi]
PST - ppublish
SO  - Cancer. 2004 Feb 15;100(4):657-66. doi: 10.1002/cncr.20026.