PMID- 19073969
OWN - NLM
STAT- MEDLINE
DCOM- 20090106
LR  - 20230610
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 14
IP  - 24
DP  - 2008 Dec 15
TI  - Inhibition of Mammalian target of rapamycin by rapamycin causes the regression of 
      carcinogen-induced skin tumor lesions.
PG  - 8094-101
LID - 10.1158/1078-0432.CCR-08-0703 [doi]
AB  - PURPOSE: The activation of Akt/mammalian target of rapamycin (mTOR) pathway 
      represents a frequent event in squamous cell carcinoma (SCC) progression, thus 
      raising the possibility of using specific mTOR inhibitors for the treatment of 
      SCC patients. In this regard, blockade of mTOR with rapamycin prevents the growth 
      of human head and neck SCC cells when xenotransplanted into immunodeficient mice. 
      However, therapeutic responses in xenograft tumors are not always predictive of 
      clinical anticancer activity. EXPERIMENTAL DESIGN: As genetically defined and 
      chemically induced animal cancer models often reflect better the complexity of 
      the clinical setting, we used here a two-step chemical carcinogenesis model to 
      explore the effectiveness of rapamycin for the treatment of skin SCC. RESULTS: 
      Rapamycin exerted a remarkable anticancer activity in this chemically induced 
      cancer model, decreasing the tumor burden of mice harboring early and advanced 
      tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumor 
      biopsies and clustering analysis revealed that rapamycin causes the rapid 
      decrease in the phosphorylation status of mTOR targets followed by the apoptotic 
      death of cancer cells and the reduction in the growth and metabolic activity of 
      the surviving ones, concomitant with a decrease in the population of cancer cells 
      expressing mutant p53. This approach enabled investigating the relationship among 
      molecular changes caused by mTOR inhibition, thus helping identify relevant 
      biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical 
      setting. CONCLUSIONS: Together, these findings provide a strong rationale for the 
      early evaluation of mTOR inhibitors as a molecular targeted approach to treat 
      SCC.
FAU - Amornphimoltham, Panomwat
AU  - Amornphimoltham P
AD  - Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental 
      Research, NIH, Bethesda, Maryland 20892-4330, USA.
FAU - Leelahavanichkul, Kantima
AU  - Leelahavanichkul K
FAU - Molinolo, Alfredo
AU  - Molinolo A
FAU - Patel, Vyomesh
AU  - Patel V
FAU - Gutkind, J Silvio
AU  - Gutkind JS
LA  - eng
GR  - ZIA DE000558/ImNIH/Intramural NIH HHS/United States
GR  - ZIA DE000558-19/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
DEP - 20081210
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carrier Proteins)
RN  - 57-97-6 (9,10-Dimethyl-1,2-benzanthracene)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 9,10-Dimethyl-1,2-benzanthracene
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Carrier Proteins/*antagonists & inhibitors
MH  - Female
MH  - Mice
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & inhibitors
MH  - Sirolimus/*pharmacology
MH  - Skin Neoplasms/chemically induced/*drug therapy/pathology
MH  - TOR Serine-Threonine Kinases
PMC - PMC3407681
MID - NIHMS236750
EDAT- 2008/12/17 09:00
MHDA- 2009/01/07 09:00
PMCR- 2012/07/29
CRDT- 2008/12/18 09:00
PHST- 2008/12/18 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/01/07 09:00 [medline]
PHST- 2012/07/29 00:00 [pmc-release]
AID - 1078-0432.CCR-08-0703 [pii]
AID - 10.1158/1078-0432.CCR-08-0703 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2008 Dec 15;14(24):8094-101. doi: 10.1158/1078-0432.CCR-08-0703. 
      Epub 2008 Dec 10.