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.