Chemoprevention and Modulation of Molecular Biomarkers in Mouse Lung Tumors
Targretin was tested for its ability to prevent lung tumors in A/J mice induced by vinyl carbamate. Doses 30-300 mg/kg decreased tumors multiplicity by greater than 19%. Administering 200 mg/kg Targretin from weeks 4-19 and 4-25 decreased the multiplicity of tumors from 35.3 ± 1.43 to 29.1 ± 1.51 and 25.0 ± 0.93, respectively. Targretin decreased tumor size in 4-25 and 23-25 wk prevented and reversed DNA hypomethylation in lung tumors. Microarrays analysis indicated that Targretin short-term treatment had a greater effect on mRNA expression than long-term treatment. In lung tumors, Targretin decreased expression of p16INK4, EP3, Caspase-3, Dnmt-3, survivin, Cyclin B2, Cyclin E1, iNOS and ER-"?", with short-term treatment being more effective than long-term treatment. Short-term treatment increased expression of Apolipoprotein D, Cyp26b, and Fabp-4, while long-term treatment only increased expression of Apolipoprotein D and Cyp26b. Budesonide and R115777 were evaluated for their usefulness in preventing vinyl carbamate-induced lung tumors in A/J mice. One week after the second dose of vinyl carbamate, mice received 60 or 100 mg/kg R115777 (gavage), 0.8 or 1.6 mg/kg budesonide (diet), or the two drugs combined treatment until sacrificed at 20, 28 and 36 weeks. Other mice received the drugs for two weeks prior to sacrifice at 20 wk. The rank order for prevention of lung tumors was the combined treatment > budesonide > R115777 (only at 20 wk). The drugs prevented DNA hypomethylation in lung tumors. While p21waf1/cip1 and Hoxa5 were methylated, APC, EGFR, RAR-"?", DAPK and Fhit genes were not.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:lung cancer chemoprevention surrogate end point biomarkers dna methylation mouse tumors
Date of Publication:01/01/2005