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

Abstract

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.

• Authors: William T Gunning, Paula M Kramer, Ronald A Lubet, Vernon E Steele, David W End, Walter Wouters, Michael A Pereira
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 5 Pg. 1927-30 (May 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12738751 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Quinolones
• Benzo(a)pyrene
• Alkyl and Aryl Transferases
• p21(ras) farnesyl-protein transferase
• tipifarnib

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (therapeutic use)
• Benzo(a)pyrene (toxicity)
• Chemoprevention
• Enzyme Inhibitors (therapeutic use)
• Female
• Lung Neoplasms (chemically induced, prevention & control)
• Mice
• Mice, Inbred A
• Quinolones (therapeutic use)