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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3271-3277. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-08-2764. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2764v1 103/9/3271    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Alsina, M. Articles by Sebti, S. M. Search for Related Content PubMed PubMed Citation Articles by Alsina, M. Articles by Sebti, S. M. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Signal Transduction Free Research Articles Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma Melissa Alsina, Rafael Fonseca, Edward F. Wilson, A. Nelida Belle, Elvira Gerbino, Tammy Price-Troska, Rose M. Overton, Gregory Ahmann, Laura M. Bruzek, Alex A. Adjei, Scott H. Kaufmann, John J. Wright, Daniel Sullivan, Benjamin Djulbegovic, Alan B. Cantor, Philip R. Greipp, William S. Dalton, and Saïd M. Sebti From the Experimental Therapeutics Program, H. Lee Moffitt Cancer Center & Research Institute and the Department of Oncology, University of South Florida, Tampa; Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute and the Department of Oncology, University of South Florida, Tampa; Division of Hematology and Department of Internal Medicine, Mayo Clinic, Rochester, MN; Division of Hematology and Department of Oncology, Mayo Clinic, Rochester, MN; and National Cancer Institute, Bethesda, MD. Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways. (Blood. 2004;103:3271-3277) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Myeloma: targeted therapies march on Martin H. Kropff and Joachim Kienast Blood 2004 103: 3247-3248. [Full Text] [PDF] This article has been cited by other articles: C. Coffinier, S. E. Hudon, R. Lee, E. A. Farber, C. Nobumori, J. H. Miner, D. A. Andres, H. P. Spielmann, C. A. Hrycyna, L. G. Fong, et al. A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells J. Biol. Chem., April 11, 2008; 283(15): 9797 - 9804. [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. 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