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 killed at 20, 28 and 36 weeks after administering the
vinyl carbamate. Other mice were administered the drugs for 2 weeks before killing at 20 weeks. At Week 20, the rank order for prevention of lung
tumors was the combined treatment>
budesonide>
R115777. At later killings,
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
R115777 produced 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 endpoint biomarker for prevention.