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[Cancer Research 61, 131-137, January 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Characterization of the Antitumor Effects of the Selective Farnesyl Protein Transferase Inhibitor R115777 in Vivo and in Vitro

David W. End1, Gerda Smets, Alison V. Todd, Tanya L. Applegate, Caroline J. Fuery, Patrick Angibaud, Marc Venet, Gerard Sanz, Herve Poignet, Stacy Skrzat, Ann Devine, Walter Wouters and Charles Bowden

Department of Medicinal Chemistry, Janssen Research Foundation, Val De Reuil 27106, France [M. V., H. P., P. A., G. S.]; Department of Oncology, Janssen Research Foundation, Beerse B2340, Belgium [G. S., W. W.]; Johnson and Johnson Research Pty., Ltd., Strawberry Hills, New South Wales 2011, Australia [A. V. T., T. L. A., C. J. F.]; and Department of Oncology, Janssen Research Foundation, Spring House, Pennsylvania 19477 [D. W. E., S. S., A. D., C. B.]

R115777 {(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone} is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, ~75% were found to be sensitive to R115777. The majority of sensitive cell lines had a wild-type ras gene. Tumor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777. Tumor cell lines bearing mutant K-ras genes required higher concentrations for inhibition of cell growth, with 50% of the cell lines resistant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation. However, inhibition of K-RasB protein-processing could not be detected. Oral administration b.i.d. of R115777 to nude mice bearing s.c. tumors at doses ranging from 6.25–100 mg/kg inhibited the growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras genes. Histological evaluations revealed heterogeneity in tumor responses to R115777. In LoVo human colon tumors, treatment with R115777 produced a prominent antiangiogenic response. In CAPAN-2 human pancreatic tumors, an antiproliferative response predominated, whereas in C32 human melanoma, marked induction of apoptosis was observed. The heterogeneity of histological changes associated with antitumor effects suggested that R115777, and possibly farnesyl protein transferase inhibitors as a class, alter processes of transformation related to tumor-host interactions in addition to inhibiting tumor-cell proliferation.




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 Molecular Cancer TherapeuticsHome page
D. M. Beaupre, E. Cepero, E. A. Obeng, L. H. Boise, and M. G. Lichtenheld
R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways
Mol. Cancer Ther., February 1, 2004; 3(2): 179 - 186.
[Abstract] [Full Text] [PDF]

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 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]

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 BloodHome page
R. Kurzrock, H. M. Kantarjian, J. E. Cortes, N. Singhania, D. A. Thomas, E. F. Wilson, J. J. Wright, E. J. Freireich, M. Talpaz, and S. M. Sebti
Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting
Blood, December 15, 2003; 102(13): 4527 - 4534.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. Delmas, D. End, P. Rochaix, G. Favre, C. Toulas, and E. Cohen-Jonathan
The Farnesyltransferase Inhibitor R115777 Reduces Hypoxia and Matrix Metalloproteinase 2 Expression in Human Glioma Xenograft
Clin. Cancer Res., December 1, 2003; 9(16): 6062 - 6068.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. E. Lancet and J. E. Karp
Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy
Blood, December 1, 2003; 102(12): 3880 - 3889.
[Abstract] [Full Text] [PDF]

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 BloodHome page
N. Ochiai, R. Uchida, S.-i. Fuchida, A. Okano, M. Okamoto, E. Ashihara, T. Inaba, N. Fujita, H. Matsubara, and C. Shimazaki
Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro
Blood, November 1, 2003; 102(9): 3349 - 3353.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. Patnaik, S. G. Eckhardt, E. Izbicka, A. A. Tolcher, L. A. Hammond, C. H. Takimoto, G. Schwartz, H. McCreery, A. Goetz, M. Mori, et al.
A Phase I, Pharmacokinetic, and Biological Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Gemcitabine in Patients with Advanced Malignancies
Clin. Cancer Res., October 15, 2003; 9(13): 4761 - 4771.
[Abstract] [Full Text] [PDF]

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 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]

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 JCOHome page
S. R.D. Johnston, T. Hickish, P. Ellis, S. Houston, L. Kelland, M. Dowsett, J. Salter, B. Michiels, J. J. Perez-Ruixo, P. Palmer, et al.
Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer
J. Clin. Oncol., July 1, 2003; 21(13): 2492 - 2499.
[Abstract] [Full Text] [PDF]

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 JCOHome page
A. A. Adjei, A. Mauer, L. Bruzek, R. S. Marks, S. Hillman, S. Geyer, L. J. Hanson, J. J. Wright, C. Erlichman, S. H. Kaufmann, et al.
Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non-Small-Cell Lung Cancer
J. Clin. Oncol., May 1, 2003; 21(9): 1760 - 1766.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
W. T. Gunning, P. M. Kramer, R. A. Lubet, V. E. Steele, D. W. End, W. Wouters, and M. A. Pereira
Chemoprevention of Benzo(a)pyrene-induced Lung Tumors in Mice by the Farnesyltransferase Inhibitor R115777
Clin. Cancer Res., May 1, 2003; 9(5): 1927 - 1930.
[Abstract] [Full Text] [PDF]

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 JCOHome page
S. J. Cohen, L. Ho, S. Ranganathan, J. L. Abbruzzese, R. K. Alpaugh, M. Beard, N. L. Lewis, S. McLaughlin, A. Rogatko, J. J. Perez-Ruixo, et al.
Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma
J. Clin. Oncol., April 1, 2003; 21(7): 1301 - 1306.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
M. Cristofanilli, A. U. Buzdar, and G. N. Hortobagyi
Update on the Management of Inflammatory Breast Cancer
Oncologist, April 1, 2003; 8(2): 141 - 148.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
S. McKenna and M. Eatock
The Medical Management of Pancreatic Cancer: A Review
Oncologist, April 1, 2003; 8(2): 149 - 160.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. Cortes, M. Albitar, D. Thomas, F. Giles, R. Kurzrock, A. Thibault, W. Rackoff, C. Koller, S. O'Brien, G. Garcia-Manero, et al.
Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies
Blood, March 1, 2003; 101(5): 1692 - 1697.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S. R. D. Johnston, J. Head, S. Pancholi, S. Detre, L.-A. Martin, I. E. Smith, and M. Dowsett
Integration of Signal Transduction Inhibitors with Endocrine Therapy: An Approach to Overcoming Hormone Resistance in Breast Cancer
Clin. Cancer Res., January 1, 2003; 9(1): 524S - 532S.
[Abstract] [Full Text] [PDF]

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 Br Med BullHome page
J. S de Bono and E. K Rowinsky
Therapeutics targeting signal transduction for patients with colorectal carcinoma
Br. Med. Bull., December 1, 2002; 64(1): 227 - 254.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
E. Fox, G. A. Curt, and F. M. Balis
Clinical Trial Design for Target-Based Therapy
Oncologist, October 1, 2002; 7(5): 401 - 409.
[Abstract] [Full Text] [PDF]

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 JCOHome page
G. K. Dy and A. A. Adjei
Novel Targets for Lung Cancer Therapy: Part I
J. Clin. Oncol., June 15, 2002; 20(12): 2881 - 2894.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Crul, G. J. de Klerk, M. Swart, L. J. van't Veer, D. de Jong, L. Boerrigter, P. A. Palmer, C. J. Bol, H. Tan, G. C. de Gast, et al.
Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer
J. Clin. Oncol., June 1, 2002; 20(11): 2726 - 2735.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
V. Smith, M. G. Rowlands, E. Barrie, P. Workman, and L. R. Kelland
Establishment and Characterization of Acquired Resistance to the Farnesyl Protein Transferase Inhibitor R115777 in a Human Colon Cancer Cell Line
Clin. Cancer Res., June 1, 2002; 8(6): 2002 - 2009.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
J. D. Wayne, E. K. Abdalla, R. A. Wolff, C. H. Crane, P. W.T. Pisters, and D. B. Evans
Localized Adenocarcinoma of the Pancreas: The Rationale for Preoperative Chemoradiation
Oncologist, February 1, 2002; 7(1): 34 - 45.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
L. R. Kelland, V. Smith, M. Valenti, L. Patterson, P. A. Clarke, S. Detre, D. End, A. J. Howes, M. Dowsett, P. Workman, et al.
Preclinical Antitumor Activity and Pharmacodynamic Studies with the Farnesyl Protein Transferase Inhibitor R115777 in Human Breast Cancer
Clin. Cancer Res., November 1, 2001; 7(11): 3544 - 3550.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
W. C. Rose, F. Y. F. Lee, C. R. Fairchild, M. Lynch, T. Monticello, R. A. Kramer, and V. Manne
Preclinical Antitumor Activity of BMS-214662, a Highly Apoptotic and Novel Farnesyltransferase Inhibitor
Cancer Res., October 1, 2001; 61(20): 7507 - 7517.
[Abstract] [Full Text] [PDF]

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 Sci SignalHome page
N. R. Gough
Signal Transduction Pathways as Targets for Therapeutics
Sci. Signal., April 3, 2001; 2001 (76): pe1 - pe1.
[Abstract] [Full Text] [PDF]


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