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Chemoprevention of Benzo(a)pyrene-induced Lung Tumors in Mice by the Farnesyltransferase Inhibitor R115777¹

Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614 [W. T. G., P. M. K., M. A. P.]; Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [R. A. L., V. E. S.]; Janssen Research Foundation, Spring House, Pennsylvania 19477 [D. W. E.]; and Janssen Research Foundation, Beerse, Belgium [W. W.]

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-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-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-Rasoncogene.

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