SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on August 28, 2003; DOI 10.1182/blood-2002-11-3359. This Article Full Text (PDF) All Versions of this Article: 2002-11-3359v1 102/13/4527    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kurzrock, R. Articles by Sebti, S. M Search for Related Content PubMed PubMed Citation Articles by Kurzrock, R. Articles by Sebti, S. M Social Bookmarking                   What's this? Submitted November 7, 2002 Accepted August 5, 2003 Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase I setting Razelle Kurzrock*, Hagop M Kantarjian, Jorge E Cortes, Neil Singhania, Deborah A Thomas, Edward F Wilson, John J Wright, Emil J Freireich, Moshe Talpaz, and Said M Sebti Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Department of Internal Medicine, University of Colorado Health Science Center, Denver, CO, USA Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA National Cancer Institute, National Institutes of Health, Bethesda, MD, USA * Corresponding author; email: rkurzroc{at}mdanderson.org. R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase I study (3+3 design) of R115777 in patients with myelodyplastic syndromes (MDS). R115777 was administered twice daily (three weeks on/one week off schedule for eight weeks) (starting dose = 300mg p.o. b.i.d. [total=600mg]). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one MDS patients were treated (median age = 66 years). Four patients (19%) had ras mutations (n-ras = 3; k-ras = 1). Objective responses (hematologic improvement [N=3], partial remission [N=2] or complete remission [N=1]) were seen in six of 20 evaluable patients (30%), only two of whom had RAS mutations. Response sequence was unusual in some patients who had rises in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400mg po bid. The most frequent side effect was myelosuppression. Dose limiting toxicities (fatigue and confusion) occurred at 900mg po total daily dose. R115777 inhibited HDJ-2 prenylation, and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk and STAT3 phosphorylation was variable and responses occurred even without their downregulation. Reduction in serum TNF- levels by day 7 showed a trend towards correlation with response (p = 0.09). We conclude that, at doses that are well-tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. S. Hong, S. M. Sebti, R. A. Newman, M. A. Blaskovich, L. Ye, R. F. Gagel, S. Moulder, J. J. Wheler, A. Naing, N. M. Tannir, et al. Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies Clin. Cancer Res., November 15, 2009; 15(22): 7061 - 7068. [Abstract] [Full Text] [PDF] J. E. Karp, K. Flatten, E. J. Feldman, J. M. Greer, D. A. Loegering, R. M. Ricklis, L. E. Morris, E. Ritchie, B. D. Smith, V. Ironside, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Blood, May 14, 2009; 113(20): 4841 - 4852. [Abstract] [Full Text] [PDF] D. S. Hong, S. B. Reddy, V. G. Prieto, J. J. Wright, N. M. Tannir, P. R. Cohen, A. H. Diwan, H. L. Evans, and R. Kurzrock Multiple Squamous Cell Carcinomas of the Skin After Therapy With Sorafenib Combined With Tipifarnib Arch Dermatol, June 1, 2008; 144(6): 779 - 782. [Abstract] [Full Text] [PDF] J. E. Karp, B. D. Smith, I. Gojo, J. E. Lancet, J. Greer, M. Klein, L. Morris, M. J. Levis, S. D. Gore, J. J. Wright, et al. Phase II Trial of Tipifarnib as Maintenance Therapy in First Complete Remission in Adults with Acute Myelogenous Leukemia and Poor-Risk Features Clin. Cancer Res., May 15, 2008; 14(10): 3077 - 3082. [Abstract] [Full Text] [PDF] D. Hong, L. Ye, R. Gagel, L. Chintala, A. K. El Naggar, J. Wright, and R. Kurzrock Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib Mol. Cancer Ther., May 1, 2008; 7(5): 1001 - 1006. [Abstract] [Full Text] [PDF] R. Kurzrock, H. M. Kantarjian, M. A. Blascovich, C. Bucher, S. Verstovsek, J. J. Wright, S. R. Pilat, J. E. Cortes, E. H. Estey, F. J. Giles, et al. Phase I Study of Alternate-Week Administration of Tipifarnib in Patients with Myelodysplastic Syndrome Clin. Cancer Res., January 15, 2008; 14(2): 509 - 514. [Abstract] [Full Text] [PDF] P. Fenaux, A. Raza, G. J. Mufti, C. Aul, U. Germing, H. Kantarjian, L. Cripe, R. Kerstens, P. De Porre, and R. Kurzrock A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome Blood, May 15, 2007; 109(10): 4158 - 4163. [Abstract] [Full Text] [PDF] J. E. Lancet, I. Gojo, J. Gotlib, E. J. Feldman, J. Greer, J. L. Liesveld, L. M. Bruzek, L. Morris, Y. Park, A. A. Adjei, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia Blood, February 15, 2007; 109(4): 1387 - 1394. [Abstract] [Full Text] [PDF] W. S. Siegel-Lakhai, M. Crul, P. De Porre, S. Zhang, I. Chang, H. Boot, J. H. Beijnen, and J. H.M. Schellens Clinical and Pharmacologic Study of the Farnesyltransferase Inhibitor Tipifarnib in Cancer Patients With Normal or Mildly or Moderately Impaired Hepatic Function J. Clin. Oncol., October 1, 2006; 24(28): 4558 - 4564. [Abstract] [Full Text] [PDF] J. A. Sparano, S. Moulder, A. Kazi, L. Vahdat, T. Li, C. Pellegrino, P. Munster, M. Malafa, D. Lee, S. Hoschander, et al. Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide J. Clin. Oncol., July 1, 2006; 24(19): 3013 - 3018. [Abstract] [Full Text] [PDF] X. Xue, K.-T. A. Lai, J.-F. Huang, Y. Gu, L. Karlsson, and A. Fourie Anti-Inflammatory Activity in Vitro and in Vivo of the Protein Farnesyltransferase Inhibitor Tipifarnib J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 53 - 60. [Abstract] [Full Text] [PDF] 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] T. F. Cloughesy, J. Kuhn, H. I. Robins, L. Abrey, P. Wen, K. Fink, F. S. Lieberman, M. Mehta, S. Chang, A. Yung, et al. Phase I Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Taking Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study J. Clin. Oncol., September 20, 2005; 23(27): 6647 - 6656. [Abstract] [Full Text] [PDF] 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] K. Zhu, E. Gerbino, D. M. Beaupre, P. A. Mackley, C. Muro-Cacho, C. Beam, A. D. Hamilton, M. G. Lichtenheld, W. G. Kerr, W. Dalton, et al. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells Blood, June 15, 2005; 105(12): 4759 - 4766. [Abstract] [Full Text] [PDF] V. Papadimitrakopoulou, S. Agelaki, H. T. Tran, M. Kies, R. Gagel, R. Zinner, E. Kim, G. Ayers, J. Wright, and F. Khuri Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4151 - 4159. [Abstract] [Full Text] [PDF] J. Cortes, S. Faderl, E. Estey, R. Kurzrock, D. Thomas, M. Beran, G. Garcia-Manero, A. Ferrajoli, F. Giles, C. Koller, et al. Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes J. Clin. Oncol., April 20, 2005; 23(12): 2805 - 2812. [Abstract] [Full Text] [PDF] K. Venkatasubbarao, A. Choudary, and J. W. Freeman Farnesyl Transferase Inhibitor (R115777)-Induced Inhibition of STAT3(Tyr705) Phosphorylation in Human Pancreatic Cancer Cell Lines Require Extracellular Signal-Regulated Kinases Cancer Res., April 1, 2005; 65(7): 2861 - 2871. [Abstract] [Full Text] [PDF] A. Cesario, A. Catassi, L. Festi, A. Imperatori, A. Pericelli, D. Galetta, S. Margaritora, V. Porziella, V. Cardaci, P. Granone, et al. Farnesyltransferase Inhibitors and Human Malignant Pleural Mesothelioma: A First-Step Comparative Translational Study Clin. Cancer Res., March 1, 2005; 11(5): 2026 - 2037. [Abstract] [Full Text] [PDF] J. V. Heymach, D. H. Johnson, F. R. Khuri, H. Safran, L. L. Schlabach, F. Yunus, R. F. DeVore III, P. M. De Porre, H. M. Richards, X. Jia, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer Ann. Onc., August 1, 2004; 15(8): 1187 - 1193. [Abstract] [Full Text] [PDF] M. Alsina, R. Fonseca, E. F. Wilson, A. N. Belle, E. Gerbino, T. Price-Troska, R. M. Overton, G. Ahmann, L. M. Bruzek, A. A. Adjei, et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma Blood, May 1, 2004; 103(9): 3271 - 3277. [Abstract] [Full Text] [PDF] R. Kurzrock, M. Albitar, J. E. Cortes, E. H. Estey, S. H. Faderl, G. Garcia-Manero, D. A. Thomas, F. J. Giles, M. E. Ryback, A. Thibault, et al. Phase II Study of R115777, a Farnesyl Transferase Inhibitor, in Myelodysplastic Syndrome J. Clin. Oncol., April 1, 2004; 22(7): 1287 - 1292. [Abstract] [Full Text] [PDF] D. P. Ryan, J. P. Eder Jr., T. Puchlaski, M. V. Seiden, T. J. Lynch, C. S. Fuchs, P. C. Amrein, D. Sonnichsen, J. G. Supko, and J. W. Clark Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors Clin. Cancer Res., April 1, 2004; 10(7): 2222 - 2230. [Abstract] [Full Text] [PDF] A. F. List, J. Vardiman, J.-P. J. Issa, and T. M. DeWitte Myelodysplastic Syndromes Hematology, January 1, 2004; 2004(1): 297 - 317. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020