Faculty Collaboration Database

Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 2003 Sep 18;22(40):6257-65

Date

09/19/2003

Pubmed ID

13679864

DOI

10.1038/sj.onc.1206630

Scopus ID

2-s2.0-0142088857 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Mutations in the Kras2 gene are seen in both human and mouse lung adenocarcinomas. The protein product (p21ras) encoded by the Kras2 gene must be post-translationally modified at a terminal CAAX motif in order to be biologically active. In this study, we systematically investigated the chemopreventive efficacy of two different farnesyltransferase inhibitors (FTIs): one is a peptidomimetic (FTI-276) and the other is an imidazole (L778-123). Both FTIs are designed to inhibit the post-translational modification of p21ras proteins with a terminal CAAX motif. In a complete chemoprevention study, where the inhibitor was administered before carcinogen was given, and throughout the study, FTI-276 treatment significantly reduced both the tumor multiplicity by 41.7% (P<0.005), and the total tumor volume by 79.4% (P<0.0001). In the late treatment study, where mice were treated with an inhibitor 12 to 20 weeks after carcinogen administration, FTI-276 treatment resulted in a 60% reduction in tumor multiplicity and 58% reduction in tumor volume. Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf. Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an approximately 50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes. Interestingly, tumor volume was decreased approximately 50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased approximately 75% in animals with a dominant-negative p53 and in mice with both a p53 mutation and heterozygous deletion of Ink4a/Arf. This result suggests that FTI exhibited a significantly (P<0.05) more efficacious chemopreventive effect in animals with alterations of p53 and Ink4a/Arf as contrasted with wild-type mice. Thus, FTIs are potent lung chemopreventive agents in both A/J mice and transgenic mice harboring a dominant-negative p53 and heterozygous deletion of Ink4a/Arf. In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals.

Author List

Zhang Z, Wang Y, Lantry LE, Kastens E, Liu G, Hamilton AD, Sebti SM, Lubet RA, You M

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Alkyl and Aryl Transferases
Animals
Anticarcinogenic Agents
Cyclin-Dependent Kinase Inhibitor p16
Enzyme Inhibitors
Farnesyltranstransferase
Gene Deletion
Genes, Dominant
Genes, p53
Heterozygote
Imidazoles
Lung Neoplasms
Methionine
Mice
Mice, Inbred A
Mice, Knockout
Mice, Transgenic