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Carcinogenesis |
Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [Z. Z., Q. L., L. E. L., Y. W., M. Y.]; Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892 [G. J. K., R. A. L.]; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267 [M. W. A.]; and Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [R. W. W.]
Recent evidence indicates that individuals with a p53 germ-line mutation
(Li-Fraumeni syndrome) have a 50% risk of developing lung cancer by
age 60. In this study, p53 heterozygous knockout mice and p53
transgenic mice carrying a dominant negative mutant were crossed with
the A/J mouse, which is highly susceptible to lung tumor induction, to
investigate whether a p53 germ-line mutation is a
predisposing gene for carcinogen-induced pulmonary adenomas in mice.
The number of lung tumors was not significantly increased in (TSG-p53
x A/J)F1 p53 heterozygous knockout mice as compared
with that in (TSG-p53 x A/J)F1 wt mice 16
weeks after exposure to N-nitrosomethylurea (MNU). In
contrast, an average of 22 lung tumors were observed in
(UL53–3 x A/J)F1 mice carrying a mutant
p53 transgene (135Valp53) compared with
an average of 7 lung tumors seen in (UL53–3 x A/J)F1 wt mice after treatment with
N-nitrosomethylurea. Similar enhancement of lung
tumor multiplicity (
3-fold) was seen when mutant
versus wt mice were treated with the tobacco-related
carcinogens benzo[a]pyrene or
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest
that the mutant p53 transgene may have a dominant
negative effect on the wt p53. The potential usefulness
of this new mouse model in lung cancer chemoprevention and chemotherapy
was examined. The chemopreventive efficacy of the green tea or a
combination of dietary dexamethasone and myo-inositol
and the chemotherapeutic efficacy of Taxol or Adriamycin was examined
in wt mice or mice with a mutation in the p53 gene. Mice
treated with dexamethasone/myo-inositol and green tea
displayed an average of 70 and 50% inhibition of lung tumors,
respectively, regardless of p53 status. Similarly, when
mice bearing established lung adenomas were treated with Taxol or
Adriamycin, a decrease in tumor volume of 70% was observed
independent of p53 mutation status. Thus, the
(UL53–3 x A/J)F1 p53
transgenic mouse seems to be an excellent model for human carriers of
p53 germ-line mutations (Li-Fraumeni syndrome). Furthermore, the lung
adenomas generated in this model possess mutations in both the
K-ras proto-oncogene and the p53 tumor
suppressor gene. This model should prove directly useful for
chemoprevention and chemotherapy studies.
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