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Carcinogenesis Advance Access published online on May 29, 2006
Carcinogenesis, doi:10.1093/carcin/bgl088
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received February 22, 2006
Revised April 12, 2006
Accepted May 19, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Prevention of mouse lung tumors and modulation of DNA methylation by combined treatment with budesonide and R115777 (ZarnestraMT)

Fadel S. Alyaqoub 1, Lianhui Tao 2, Paula M. Kramer 1, Vernon E. Steele 3, Ronald A. Lubet 3, William T. Gunning 1, and Michael A. Pereira 2 *

1 Medical University of Ohio, Toledo, OH 43614
2 Medical University of Ohio, Toledo, OH 43614; Ohio State University, College of Medicine and Public Health, Columbus, OH 43210
3 National Cancer Institute, Bethesda, MD 20892

* To whom correspondence should be addressed.
Michael A. Pereira, E-mail: Pereira.25{at}osu.edu


  Abstract

Budesonide (an anti-inflammatory glucocorticoid), R115777 (a farnesyl transferase inhibitor, Zarnestra, Tipifarnib), or combinations of them were evaluated for prevention of lung tumors and for modulation of DNA methylation in tumors. Lung tumors were induced by vinyl carbamate in female Strain A mice. One week later, mice received 60 or 100 mg/kg R115777 by oral gavage and 5 days/week, 0.8 or 1.6 mg/kg of budesonide in their diet, or their combined treatment until sacrificed at 20, 28 and 36 weeks after administering the vinyl carbamate. Other mice were administered the drugs for two weeks prior to sacrifice at 20 weeks. At Week 20, the rank order for prevention of lung tumors was the combined treatment > budesonide > R115777. At later sacrifices, R115777 was no longer effective, whereas budesonide and the combinations continued to prevent tumors, albeit at a reduced efficacy. DNA hypomethylation in lung tumors was prevented by treatment with R115777, budesonide, and the combinations. When administered starting at Week 18 to tumor-bearing mice, the drugs reversed DNA hypomethylation in the tumors. In summary, combined treatment with budesonide and R115777produced the following results: i) it was more efficacious in preventing lung tumors than the individual drugs; and ii) it prevented and reversed DNA hypomethylation in lung tumors. These results support the combined use of budesonide and R115777 in prevention of lung tumors and suggest that reversal of DNA hypomethylation in lung tumors would be useful as a surrogate end-point biomarker for prevention.


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