Chemoprevention: mouse colon and lung tumor bioassay and modulation of DNA methylation as a biomarker.
Lung and colon tumors were induced in A/J, C3H, and A/J X C3H (AC3) mice by administering 16 mg/kg vinyl carbamate followed by 6 weekly doses of 12 mg/kg azoxymethane (AOM). Beginning 1 week after carcinogen treatment, the mice received chemopreventive agents, dexamethasone or piroxicam, at 0.1 and 75 mg/kg in the diet, respectively. Both AOM and vinyl carbamate induces lung tumors, but only AOM induced colon tumors. The strain sensitivity for both colon and lung tumors was A/J > AC3 > C3H mice. Dexamethasone and piroxicam reduced the multiplicity of colon and lung tumors in A/J and AC3 mice, demonstrating the advantage of a combined colon and lung bioassay. The ability of budesonide, a drug that prevents mouse lung tumors, to modulate DNA methylation in vinyl carbamate-induced lung tumors was also determined. Budesonide administered for only 7 days prior to sacrifice caused a dose-dependent (0.6 to 2.4 mg/kg diet) reversal in tumors of DNA hypomethylation and hypomethylation of the insulin-like growth factor (IGF)-II gene in the differentially methylated region (DMR) 2 region of exons 4 to 5. Longer treatment with budesonide reversed hypomethylation when administered up to the time of sacrifice. These results indicate that reversal of the hypomethylation of DNA and of specific genes in lung tumors may be applicable as a surrogate end-point biomarker for chemoprevention.
Pereira
Michael A
MA
Department of Pathology, Medical College of Ohio, Toledo, Ohio, USA. pereira-1@medctr.osu.edu
Tao
Lian H
LH
Wang
Wei
W
Gunning
William T
WT
Lubet
Ronald
R
D000818:Animals; D001397:Azoxymethane; D001681:Biological Assay; D015415:Biomarkers; D019819:Budesonide / Q000008:administration & dosage / Q000494:pharmacology; D002273:Carcinogens; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D019175:DNA Methylation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D010894:Piroxicam / Q000494:pharmacology; D014520:Urethane / Q000031:analogs & derivatives*
D015415:Biomarkers; D002273:Carcinogens; D005938:Glucocorticoids; D010894:Piroxicam; D014520:Urethane; D019819:Budesonide; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone; C017963:vinyl carbamate; D001397:Azoxymethane