Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 2000 Jan;21(1):113-6
Date
12/23/1999Pubmed ID
10607742DOI
10.1093/carcin/21.1.113Scopus ID
2-s2.0-0033959438 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
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.
Author List
Lantry LE, Zhang Z, Yao R, Crist KA, Wang Y, Ohkanda J, Hamilton AD, Sebti SM, Lubet RA, You MMESH terms used to index this publication - Major topics in bold
AdenomaAlkyl and Aryl Transferases
Animals
Antineoplastic Agents
Carcinogens
Enzyme Inhibitors
Genes, ras
Lung Neoplasms
Methionine
Mice
Mutation
Nitrosamines
