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

The Ras protein undergoes a series of post-translational modifications at t he C-terminal CAAX motif, which culminates with the anchoring of p21 Ras to the plasma membrane where it relays growth regulatory signals from recepto r tyrosine kinases to various pathways of cell signal transduction, FTI-276 is a CAAX peptidomimetic of the carboxyl terminal of Ras proteins. Pharmac okinetic 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 m u g/ml for up to 30 days following implantation, In the present study, 4 we ek 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 fo r 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 multipl icity and a 42% reduction in tumor incidence. Moreover, FTI-276 treatment r esulted in a significant reduction in tumor volume (similar to 58%), Mutati on analysis of the lung tumors from both treatment groups revealed that mos t 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 tum ors from the treated and control animals. This is the first demonstration o f chemotherapeutic efficacy of a synthetic CAAX peptidomimetie farnesyltran sferase inhibitor in a primary lung tumor model.