Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a\Arf

Zhongqiu Zhang, Yian Wang, Laura E. Lantry, Elizabeth Kastens, Gongjie Liu, Andrew Hamilton, Said M. Sebti, Ronald A. Lubet, Ming You

Research output: Contribution to journalArticle

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 posttranslational modification of p21 ras 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 ∼ 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 ∼ 50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased ∼ 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.

Original languageEnglish (US)
Pages (from-to)6257-6265
Number of pages9
JournalOncogene
Volume22
Issue number40
DOIs
StatePublished - Sep 18 2003

Fingerprint

Farnesyltranstransferase
Lung Neoplasms
Tumor Burden
Carcinogens
Mutation
Lung
Transgenic Mice
Neoplasms
Proto-Oncogene Proteins p21(ras)
Peptidomimetics
ras Proteins
Wild Animals
Sequence Deletion
Chemoprevention
Therapeutics
Post Translational Protein Processing
Tumor Suppressor Genes
Genes

Keywords

  • A/J mice
  • Chemoprevention
  • Farnesyltransferase inhibitor
  • Ink4a/Arf
  • Lung cancer
  • P53
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a\Arf. / Zhang, Zhongqiu; Wang, Yian; Lantry, Laura E.; Kastens, Elizabeth; Liu, Gongjie; Hamilton, Andrew; Sebti, Said M.; Lubet, Ronald A.; You, Ming.

In: Oncogene, Vol. 22, No. 40, 18.09.2003, p. 6257-6265.

Research output: Contribution to journalArticle

Zhang, Zhongqiu ; Wang, Yian ; Lantry, Laura E. ; Kastens, Elizabeth ; Liu, Gongjie ; Hamilton, Andrew ; Sebti, Said M. ; Lubet, Ronald A. ; You, Ming. / Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a\Arf. In: Oncogene. 2003 ; Vol. 22, No. 40. pp. 6257-6265.
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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 posttranslational modification of p21 ras 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 ∼ 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 ∼ 50{\%} in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased ∼ 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.",
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T1 - Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a\Arf

AU - Zhang, Zhongqiu

AU - Wang, Yian

AU - Lantry, Laura E.

AU - Kastens, Elizabeth

AU - Liu, Gongjie

AU - Hamilton, Andrew

AU - Sebti, Said M.

AU - Lubet, Ronald A.

AU - You, Ming

PY - 2003/9/18

Y1 - 2003/9/18

N2 - 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 posttranslational modification of p21 ras 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 ∼ 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 ∼ 50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased ∼ 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.

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