Cancer Research Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine Joint Metastasis Research Society-AACR Conference on Metastasis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Omer, C. A.
Right arrow Articles by Kohl, N. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Omer, C. A.
Right arrow Articles by Kohl, N. E.
[Cancer Research 60, 2680-2688, May 15, 2000]
© 2000 American Association for Cancer Research

Experimental Therapeutics

Mouse Mammary Tumor Virus-Ki-rasB Transgenic Mice Develop Mammary Carcinomas That Can Be Growth-inhibited by a Farnesyl:Protein Transferase Inhibitor

Charles A. Omer1, Zunxuan Chen2, Ronald E. Diehl, Michael W. Conner3, Howard Y. Chen, Myrna E. Trumbauer, Shobhna Gopal-Truter, Gina Seeburger, Hema Bhimnathwala, Marc T. Abrams, Joseph P. Davide, Michelle S. Ellis, Jackson B. Gibbs, Ian Greenberg4, Kelly Hamilton, Kenneth S. Koblan, Astrid M. Kral, Dongming Liu, Robert B. Lobell, Patricia J. Miller, Scott D. Mosser, Timothy J. O’Neill, Elaine Rands, Michael D. Schaber, Edith T. Senderak, Allen Oliff5 and Nancy E. Kohl6

Departments of Cancer Research [C. A. O., Z. C., R. E. D., H. B., M. T. A., J. P. D., M. S. E., J. B. G., I. G., K. H., K. S. K., A. M. K., D. L., R. B. L., P. J. M., S. D. M., T. J. O., E. R., M. D. S., A. O., N. E. K.], Safety Assessment [M. W. C.], and Biometrics Research [E. T. S.], Merck Research Laboratories, West Point, Pennsylvania 19486, and Departments of Metabolic Disorders [H. Y. C., M. E. T.] and Laboratory Animal Resources [S. G-T., G. S.], Merck Research Laboratories, Rahway, New Jersey 07065

For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Although these data support the further development of FTIs, it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers. Moreover, Ki-RasB binds more tightly to FPTase than either Ha- or N-Ras, and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing. Given the unique biochemical and biological features of Ki-RasB, it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein. We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V) under the control of the MMTV enhancer/promoter. The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detected in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity. Although FPTase activity was inhibited in tumors from the treated mice, unprocessed Ki-RasB was not detected. These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model, Ki-Ras may not be the sole mediator of the biological effects of the FTI.




This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Podsypanina, K. Politi, L. J. Beverly, and H. E. Varmus
Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras
PNAS, April 1, 2008; 105(13): 5242 - 5247.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
G. M. Zinser, M. A. Leonis, K. Toney, P. Pathrose, M. Thobe, S. A. Kader, B. E. Peace, S. R. Beauman, M. H. Collins, and S. E. Waltz
Mammary-Specific Ron Receptor Overexpression Induces Highly Metastatic Mammary Tumors Associated with {beta}-Catenin Activation
Cancer Res., December 15, 2006; 66(24): 11967 - 11974.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
A. E. Rusinol and M. S. Sinensky
Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors.
J. Cell Sci., August 15, 2006; 119(Pt 16): 3265 - 3272.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
R. Yao, Y. Wang, Y. Lu, W. J. Lemon, D. W. End, C. J. Grubbs, R. A. Lubet, and M. You
Efficacy of the farnesyltransferase inhibitor R115777 in a rat mammary tumor model: role of Ha-ras mutations and use of microarray analysis in identifying potential targets
Carcinogenesis, July 1, 2006; 27(7): 1420 - 1431.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. T. Efuet and K. Keyomarsi
Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome
Cancer Res., January 15, 2006; 66(2): 1040 - 1051.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
A. D. Basso, P. Kirschmeier, and W. R. Bishop
Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors
J. Lipid Res., January 1, 2006; 47(1): 15 - 31.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. D. Basso, A. Mirza, G. Liu, B. J. Long, W. R. Bishop, and P. Kirschmeier
The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) Inhibits Rheb Farnesylation and mTOR Signaling: ROLE IN FTI ENHANCEMENT OF TAXANE AND TAMOXIFEN ANTI-TUMOR ACTIVITY
J. Biol. Chem., September 2, 2005; 280(35): 31101 - 31108.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
N. M.G.M. Appels, J. H. Beijnen, and J. H.M. Schellens
Development of Farnesyl Transferase Inhibitors: A Review
Oncologist, September 1, 2005; 10(8): 565 - 578.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
R. Meuwissen and A. Berns
Mouse models for human lung cancer
Genes & Dev., March 15, 2005; 19(6): 643 - 664.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. R. Tan, X. Yang, S. M. Hewitt, A. Berman, E. R. Lepper, A. Sparreboom, A. L. Parr, W. D. Figg, C. Chow, S. M. Steinberg, et al.
Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
J. Clin. Oncol., August 1, 2004; 22(15): 3080 - 3090.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. O. Bergo, H. D. Lieu, B. J. Gavino, P. Ambroziak, J. C. Otto, P. J. Casey, Q. M. Walker, and S. G. Young
On the Physiological Importance of Endoproteolysis of CAAX Proteins: HEART-SPECIFIC RCE1 KNOCKOUT MICE DEVELOP A LETHAL CARDIOMYOPATHY
J. Biol. Chem., February 6, 2004; 279(6): 4729 - 4736.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Sun, J. Ohkanda, D. Coppola, H. Yin, M. Kothare, B. Busciglio, A. D. Hamilton, and S. M. Sebti
Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice
Cancer Res., December 15, 2003; 63(24): 8922 - 8929.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. W. C. J. van de Donk, D. Schotte, M. M. J. Kamphuis, A. M. W. van Marion, B. van Kessel, A. C. Bloem, and H. M. Lokhorst
Protein Geranylgeranylation Is Critical for the Regulation of Survival and Proliferation of Lymphoma Tumor Cells
Clin. Cancer Res., November 15, 2003; 9(15): 5735 - 5748.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
N. W. C. J. van de Donk, M. M. J. Kamphuis, B. van Kessel, H. M. Lokhorst, and A. C. Bloem
Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels
Blood, November 1, 2003; 102(9): 3354 - 3362.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. B. Brunner, S. M. Hahn, A. K. Gupta, R. J. Muschel, W. G. McKenna, and E. J. Bernhard
Farnesyltransferase Inhibitors: An Overview of the Results of Preclinical and Clinical Investigations
Cancer Res., September 15, 2003; 63(18): 5656 - 5668.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. L. Aiyagari, B. R. Taylor, V. Aurora, S. G. Young, and K. M. Shannon
Hematologic effects of inactivating the Ras processing enzyme Rce1
Blood, March 15, 2003; 101(6): 2250 - 2252.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
R. B. Lobell, D. Liu, C. A. Buser, J. P. Davide, E. DePuy, K. Hamilton, K. S. Koblan, Y. Lee, S. Mosser, S. L. Motzel, et al.
Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Type-I
Mol. Cancer Ther., July 1, 2002; 1(9): 747 - 758.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. L. van Golen, L. Bao, M. M. DiVito, Z. Wu, G. C. Prendergast, and S. D. Merajver
Reversion of RhoC GTPase-induced Inflammatory Breast Cancer Phenotype by Treatment with a Farnesyl Transferase Inhibitor
Mol. Cancer Ther., June 1, 2002; 1(8): 575 - 583.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. B. Lobell, C. A. Omer, M. T. Abrams, H. G. Bhimnathwala, M. J. Brucker, C. A. Buser, J. P. Davide, S. J. deSolms, C. J. Dinsmore, M. S. Ellis-Hutchings, et al.
Evaluation of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Inhibitor Combinations in Preclinical Models
Cancer Res., December 1, 2001; 61(24): 8758 - 8768.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Cohen-Jonathan, S. M. Evans, C. J. Koch, R. J. Muschel, W. G. McKenna, J. Wu, and E. J. Bernhard
The Farnesyltransferase Inhibitor L744,832 Reduces Hypoxia in Tumors Expressing Activated H-ras
Cancer Res., March 1, 2001; 61(5): 2289 - 2293.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
D. W. End, G. Smets, A. V. Todd, T. L. Applegate, C. J. Fuery, P. Angibaud, M. Venet, G. Sanz, H. Poignet, S. Skrzat, et al.
Characterization of the Antitumor Effects of the Selective Farnesyl Protein Transferase Inhibitor R115777 in Vivo and in Vitro
Cancer Res., January 1, 2001; 61(1): 131 - 137.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
H. E. Huber, R. G. Robinson, A. Watkins, D. D. Nahas, M. T. Abrams, C. A. Buser, R. B. Lobell, D. Patrick, N. J. Anthony, C. J. Dinsmore, et al.
Anions Modulate the Potency of Geranylgeranyl-Protein Transferase I Inhibitors
J. Biol. Chem., June 29, 2001; 276(27): 24457 - 24465.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2000 by the American Association for Cancer Research.