PMID- 22831276
OWN - NLM
STAT- MEDLINE
DCOM- 20130419
LR  - 20211203
IS  - 1873-5576 (Electronic)
IS  - 1568-0096 (Linking)
VI  - 12
IP  - 8
DP  - 2012 Oct
TI  - Disrupting the mTOR signaling network as a potential strategy for the enhancement 
      of cancer radiotherapy.
PG  - 899-924
AB  - Radiotherapy (RT) allows for tumor control through the cytotoxic action of 
      ionizing radiation (IR). Although modern technologies permit precise IR delivery 
      to the tumor mass while minimizing exposure of surrounding healthy tissues, the 
      efficacy of RT remains limited by the intrinsic or acquired radioresistance of 
      many tumors. There is thus an ongoing search for agents that augment the 
      sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting 
      components of signaling pathways involved in tumor growth and radioresistance. 
      Here, we review the evidence suggesting that disabling one of these components, 
      the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This 
      molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein 
      complexes, which regulate cell growth and other processes implicated in 
      tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked 
      by the microbial product rapamycin and its analogs (collectively designated 
      rapamycins) that are approved for cancer treatment, and is frequently 
      hyperactivated in malignant cells. In several, but not all human cancer cell 
      lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple 
      mechanisms, including the promotion of autophagic cell death. Rapamycins also 
      potentiated fractionated RT in tumor xenograft models, in part by suppressing 
      tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K 
      and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater 
      efficiency than rapamycins. These encouraging data have led to early clinical 
      trials of rapamycins and catalytic mTOR inhibitors combined with RT in various 
      cancers.
FAU - Dumont, Francis J
AU  - Dumont FJ
AD  - Laboratoire de Radiobiology, EA 3430, Universite de Strasbourg, Centre Regional 
      de Lutte contre le Cancer Paul Strauss, 3 rue de la Porte de l'Hopital, F-67065 
      Strasbourg, France. dumontfj@gmail.com
FAU - Bischoff, Pierre
AU  - Bischoff P
LA  - eng
PT  - Journal Article
PT  - Review
PL  - Netherlands
TA  - Curr Cancer Drug Targets
JT  - Current cancer drug targets
JID - 101094211
RN  - 0 (Radiation-Sensitizing Agents)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autophagy/drug effects
MH  - Cell Line, Tumor
MH  - DNA Repair/drug effects
MH  - Humans
MH  - Mice
MH  - Neoplasms/drug therapy/*metabolism/*radiotherapy
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/*metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/07/27 06:00
MHDA- 2013/04/23 06:00
CRDT- 2012/07/27 06:00
PHST- 2011/12/14 00:00 [received]
PHST- 2012/04/05 00:00 [revised]
PHST- 2012/05/04 00:00 [accepted]
PHST- 2012/07/27 06:00 [entrez]
PHST- 2012/07/27 06:00 [pubmed]
PHST- 2013/04/23 06:00 [medline]
AID - CCDT-EPUB-20120724-1 [pii]
AID - 10.2174/156800912803251243 [doi]
PST - ppublish
SO  - Curr Cancer Drug Targets. 2012 Oct;12(8):899-924. doi: 
      10.2174/156800912803251243.