Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors.
OBJECTIVE
Human and murine preneoplastic lung lesions induced by tobacco exposure are characterized by increased activation of the Akt/mammalian target of rapamycin (mTOR) pathway, suggesting a role for this pathway in lung cancer development. To test this, we did studies with rapamycin, an inhibitor of mTOR, in A/J mice that had been exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).


METHODS
Tumorigenesis was induced by i.p. injection of NNK, and rapamycin was administered 1 or 26 weeks after NNK administration. Biomarkers associated with mTOR inhibition were assessed in lung and/or surrogate tissues using immunohistochemistry and immunoblotting. Rapamycin levels were measured using mass spectroscopy.


RESULTS
Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR.


CONCLUSIONS
Tobacco carcinogen-induced lung tumors in A/J mice are dependent upon mTOR activity because rapamycin markedly reduced the development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.
Granville
Courtney A
CA
Medical Oncology Branch and Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
Warfel
Noel
N
Tsurutani
Junji
J
Hollander
M Christine
MC
Robertson
Matthew
M
Fox
Stephen D
SD
Veenstra
Timothy D
TD
Issaq
Haleem J
HJ
Linnoila
R Ilona
RI
Dennis
Phillip A
PA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity*; D010641:Phenotype; D011494:Protein Kinases / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases; D014026:Nicotiana / Q000737:chemistry / Q000633:toxicity
D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus