Chemoprevention of benzo(a)pyrene-induced lung tumors in mice by the farnesyltransferase inhibitor R115777.
2003
Purpose: Inhibitors of farnesyltransferase
( e.g., R115777) are being developed for therapy and
prevention of various cancers. The efficacy of R115777 [Zarnestra;
( B )-6-[amino(4-chlorophenyl)(1-methyl-1 H -imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1 H )-quinolinone]
to prevent the development of lung tumors in mice was determined. Experimental Design: Female strain A mice (7–8 weeks of
age) were given 100 mg/kg benzo( a )pyrene [B(a)P] by
i.p. injection, and 4 or 14 weeks later, they were given 50 or 100
mg/kg R115777 by oral gavage 5 days/week. The mice were sacrificed 22
weeks after they received the B(a)P. Results : Tumor multiplicity was 5.0 ± 0.85,
4.5 ± 0.52, 2.1 ± 0.31, and 1.5 ± 0.31 tumors/mouse
in mice that received 0, 50, 100 (weeks 4–22), or 100 (weeks 14–22)
mg/kg R115777. Thus, 100 mg/kg R115777 was similarly effective in
preventing lung tumors when administered during the promotional phase
of carcinogenesis [that is, either 4 or 14 weeks after B(a)P],
whereas the lower dose of 50 mg/kg R115777 was ineffective. The
proliferating cell nuclear antigen labeling index was also
significantly reduced in lung tumors from mice treated with 100 mg/kg
R115777 starting at 4 or 14 weeks. Conclusions: These results demonstrated that R115777 can
prevent the development of lung tumors in the A/J mouse model, where
tumors routinely have mutations in the Ki- Ras oncogene.
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