Chemoprevention of benzo(a)pyrene-induced lung tumors in mice by the farnesyltransferase inhibitor R115777.
OBJECTIVE
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.


METHODS
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.
Gunning
William T
WT
Department of Pathology, Medical College of Ohio, Toledo 43614, USA. wgunning@mco.edu
Kramer
Paula M
PM
Lubet
Ronald A
RA
Steele
Vernon E
VE
End
David W
DW
Wouters
Walter
W
Pereira
Michael A
MA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001564:Benzo(a)pyrene / Q000633:toxicity; D018890:Chemoprevention; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D015363:Quinolones / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D001564:Benzo(a)pyrene; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib