Reference SummaryLantry LE, Carcinogenesis 2000 Jan;21(1):113-6

Title

Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Authors

Lantry LE; Zhang Z; Yao R; Crist KA; Wang Y; Ohkanda J; Hamilton AD; Sebti SM; Lubet RA; You M

Journal

Carcinogenesis

Volume

21

Issue

1

Year

2000

Pages

113-6

Abstract

The Ras protein undergoes a series of post-translational modifications at the C-terminal CAAX motif, which culminates with the anchoring of p21 Ras to the plasma membrane where it relays growth regulatory signals from receptor tyrosine kinases to various pathways of cell signal transduction. FTI-276 is a CAAX peptidomimetic of the carboxyl terminal of Ras proteins. Pharmacokinetic analysis of FTI-276 in A/J mice with a time-release pellet system showed a dose of 50 mg/kg body wt achieved an average serum level of 1.68 microg/ml for up to 30 days following implantation. In the present study, 4 week old A/J mice were initiated with a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (100 mg/kg), and monitored for 18 weeks. Mice were grouped for daily delivery (time-release pellet) of 50 mg/kg of FTI-276 for 30 days (n = 12) and the control group (n = 12). Analysis of tumors from time-release pellet treated animals showed a 60% reduction in tumor multiplicity and a 42% reduction in tumor incidence. Moreover, FTI-276 treatment resulted in a significant reduction in tumor volume (approximately 58%). Mutation analysis of the lung tumors from both treatment groups revealed that most of the tumors harbored mutations in the codon 12 of K-ras and there is no significant difference in the incidence and types of mutations between tumors from the treated and control animals. This is the first demonstration of chemotherapeutic efficacy of a synthetic CAAX peptidomimetic farnesyltransferase inhibitor in a primary lung tumor model.

Links

J:59576 – MGI References
10607742 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
A/J Lung adenoma
  • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Lung

100

A/J Lung adenoma
  • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
  • FTI-276 (farnesyltransferase inhibitor 276)
Lung

58