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

Laura E. Lantry, Zhongqiu Zhang, Rusheng Yao, Keith A. Crist, Yian Wang, Junko Ohkanda, Andrew Hamilton, Said M. Sebti, Ronald A. Lubet, Ming You

Research output: Contribution to journalArticle

Abstract

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 μg/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 (~ 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.

Original languageEnglish (US)
Pages (from-to)113-116
Number of pages4
JournalCarcinogenesis
Volume21
Issue number1
StatePublished - 2000

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Farnesyltranstransferase
Adenoma
Lung
Neoplasms
Peptidomimetics
ras Proteins
Mutation
Proto-Oncogene Proteins p21(ras)
Incidence
Receptor Protein-Tyrosine Kinases
Post Translational Protein Processing
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
FTI 276
Tumor Burden
Codon
Signal Transduction
Pharmacokinetics
Cell Membrane
Control Groups
Growth

ASJC Scopus subject areas

  • Cancer Research

Cite this

Lantry, L. E., Zhang, Z., Yao, R., Crist, K. A., Wang, Y., Ohkanda, J., ... You, M. (2000). Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis, 21(1), 113-116.

Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. / Lantry, Laura E.; Zhang, Zhongqiu; Yao, Rusheng; Crist, Keith A.; Wang, Yian; Ohkanda, Junko; Hamilton, Andrew; Sebti, Said M.; Lubet, Ronald A.; You, Ming.

In: Carcinogenesis, Vol. 21, No. 1, 2000, p. 113-116.

Research output: Contribution to journalArticle

Lantry, LE, Zhang, Z, Yao, R, Crist, KA, Wang, Y, Ohkanda, J, Hamilton, A, Sebti, SM, Lubet, RA & You, M 2000, 'Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone', Carcinogenesis, vol. 21, no. 1, pp. 113-116.
Lantry, Laura E. ; Zhang, Zhongqiu ; Yao, Rusheng ; Crist, Keith A. ; Wang, Yian ; Ohkanda, Junko ; Hamilton, Andrew ; Sebti, Said M. ; Lubet, Ronald A. ; You, Ming. / Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. In: Carcinogenesis. 2000 ; Vol. 21, No. 1. pp. 113-116.
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abstract = "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 μg/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 (~ 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.",
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AU - Yao, Rusheng

AU - Crist, Keith A.

AU - Wang, Yian

AU - Ohkanda, Junko

AU - Hamilton, Andrew

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AU - Lubet, Ronald A.

AU - You, Ming

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