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.Key words: budesonide; biomarkers; chemoprevention; DNA hypomethylation; lung cancer; mRNA expression; mouse lung tumors The development of cancer chemopreventive and therapeutic agents would be aided by the use of biomarkers. Biomarkers have the advantage of requiring a shorter duration of treatment than either the prevention or regression of tumors. In clinical trials, the greatest utility of biomarkers appears to be in studies that determine their modulation by relatively short-term treatment with therapeutic and chemopreventive agents. Recent advances in the molecular biology of cancer have suggested several biological and molecular endpoints that might be useful as biomarkers, including DNA hypomethylation and alteration in mRNA expression of cancer-related genes.Budesonide, a synthetic anti-inflammatory glucocorticoid used to control mild-to-moderate persistent asthma, 1 has been shown to prevent the formation of lung adenomas and adenocarcinomas in mice when administered either by inhalation or in the diet. 2-7 As a chemopreventive agent, budesonide appears to decrease both the growth rate of tumors and the progression of adenomas to adenocarcinomas. 4 Lung tumors from budesonide-treated mice were smaller and contained fewer carcinomas when compared with tumors from mice that were not administered the drug. Budesonide has also been demonstrated to prevent the occurrence of DNA hypomethylation in mouse lung tumors 4,5 and to modulate the mRNA expression of cancer-related genes. 4,8 Another drug that is eff...

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