PMID- 19139015
OWN - NLM
STAT- MEDLINE
DCOM- 20090318
LR  - 20211203
IS  - 1940-6215 (Electronic)
IS  - 1940-6215 (Linking)
VI  - 2
IP  - 1
DP  - 2009 Jan
TI  - Targeting mammalian target of rapamycin by rapamycin prevents tumor progression 
      in an oral-specific chemical carcinogenesis model.
PG  - 27-36
LID - 10.1158/1940-6207.CAPR-08-0147 [doi]
AB  - The increased molecular understanding of cancerous growth may now afford the 
      opportunity to develop novel therapies targeting specific dysregulated molecular 
      mechanisms contributing to the progression of each cancer type. In this regard, 
      the aberrant activation of Akt/mammalian target of rapamycin (mTOR) pathway is a 
      frequent event in head and neck squamous cell carcinomas (HNSCC), thus 
      representing a potential molecular target for the treatment of HNSCC patients. 
      The ability to translate this emerging body of information into effective 
      therapeutic strategies, however, has been hampered by the limited availability of 
      animal models for oral malignancies. Here, we show that the administration in the 
      drinking water to mice of 4-nitroquinoline-1 oxide, a DNA adduct-forming agent 
      that serves as a surrogate of tobacco exposure, leads to the progressive 
      appearance of preneoplastic and tumoral lesions in the tongue and oral mucosa, 
      with 100% incidence after only 16 weeks of carcinogen exposure. Remarkably, many 
      of these lesions evolve spontaneously into highly malignant SCCs few weeks after 
      4-nitroquinoline-1 oxide withdrawal. In this model, we have observed that the 
      activation of the Akt-mTOR biochemical route represents an early event, which is 
      already detectable in dysplastic lesions. Furthermore, we show that the 
      inhibition of mTOR by the chronic administration of rapamycin halts the malignant 
      conversion of precancerous lesions and promotes the regression of advanced 
      carcinogen-induced SCCs. Together, these findings support the contribution of the 
      mTOR signaling pathway to HNSCC progression and provide a strong rationale for 
      the early evaluation of mTOR inhibitors as a molecular-targeted strategy for 
      HNSCC chemoprevention and treatment.
FAU - Czerninski, Rakefet
AU  - Czerninski R
AD  - Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial 
      Research, NIH, 30 Convent Drive, Building 30, Bethesda, MD 20892-4340, USA.
FAU - Amornphimoltham, Panomwat
AU  - Amornphimoltham P
FAU - Patel, Vyomesh
AU  - Patel V
FAU - Molinolo, Alfredo A
AU  - Molinolo AA
FAU - Gutkind, J Silvio
AU  - Gutkind JS
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Cancer Prev Res (Phila)
JT  - Cancer prevention research (Philadelphia, Pa.)
JID - 101479409
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Carcinogens)
RN  - 56-57-5 (4-Nitroquinoline-1-oxide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cancer Prev Res (Phila). 2009 Jan;2(1):7-9. PMID: 19139011
CIN - Cancer Prev Res (Phila). 2009 Jan;2(1):10-3. PMID: 19139012
MH  - 4-Nitroquinoline-1-oxide/toxicity
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Carcinogens/toxicity
MH  - Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology
MH  - Cell Transformation, Neoplastic/drug effects/metabolism/pathology
MH  - Disease Progression
MH  - Female
MH  - Gene Expression/drug effects
MH  - Head and Neck Neoplasms/*drug therapy/metabolism/pathology
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Precancerous Conditions/*drug therapy/metabolism/pathology
MH  - Protein Kinases/biosynthesis/*drug effects
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/01/14 09:00
MHDA- 2009/03/19 09:00
CRDT- 2009/01/14 09:00
PHST- 2009/01/14 09:00 [entrez]
PHST- 2009/01/14 09:00 [pubmed]
PHST- 2009/03/19 09:00 [medline]
AID - 2/1/27 [pii]
AID - 10.1158/1940-6207.CAPR-08-0147 [doi]
PST - ppublish
SO  - Cancer Prev Res (Phila). 2009 Jan;2(1):27-36. doi: 
      10.1158/1940-6207.CAPR-08-0147.