Modulation by budesonide of DNA methylation and mRNA expression in mouse lung tumors

Abstract

Biomarkers are being developed that can aid in the evaluation of cancer therapeutic and chemopreventive drugs. Two suggested biomarkers found in mouse lung tumors are DNA hypomethylation and alterations in mRNA expression of genes, such as 18S RNA, caspase 3, cyclin B2, cyclin E1, iNOS and survivin. Budesonide is very efficacious in preventing lung tumors in mice, so that its ability to modulate biomarkers in lung tumors was determined. Lung tumors were induced by vinyl carbamate in female strain A/J mice. Budesonide (2.0 mg/kg diet) was administered for 2, 7 and 21 days or for 14 days followed by a 7-days' holding period prior to the killing of the mice at week 27. After 2 days of budesonide treatment, the size of the lung tumors was reduced. Tumor size continued to decrease during the 21 days of treatment. In the tumors, 2 days of treatment resulted in (i) increased methylation of DNA, reversing DNA hypomethylation, (ii) increased expression of 18S RNA and (iii) decreased mRNA expression of caspase 3, cyclin B2, cyclin E1, iNOS and survivin. Termination of budesonide treatment at 7 days prior to killing did not affect the size of the tumors, but did result in increased mRNA expression of the 5 genes, approaching the expression level in tumors from control mice. Hence, budesonide rapidly decreased the size of lung tumors, reversed DNA hypomethylation and modulated mRNA expression of genes; with the molecular alterations requiring continued treatment with the drug for maintenance. © 2006 Wiley-Liss, Inc.