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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4759-4766. Prepublished online as a Blood First Edition Paper on February 22, 2005; DOI 10.1182/blood-2004-11-4307. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4307v1 105/12/4759    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 Zhu, K. Articles by Sebti, S. M. Search for Related Content PubMed PubMed Citation Articles by Zhu, K. Articles by Sebti, S. M. Related Collections Neoplasia Apoptosis Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells Kuichun Zhu, Elvira Gerbino, Darrin M. Beaupre, Paul A. Mackley, Carlos Muro-Cacho, Craig Beam, Andrew D. Hamilton, Mathias G. Lichtenheld, William G. Kerr, William Dalton, Melissa Alsina, and Saïd M. Sebti From the Drug Discovery Program, the Experimental Therapeutics Program and Immunology Program, Biostatistics Core, H. Lee Moffitt Cancer Center & Research Institute and the Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL; the Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; and Yale University, Department of Chemistry, New Haven, CT. Despite major advances, multiple myeloma (MM) remains an incurable malignancy. Recently we have found that disease stabilization was achieved in 64% of patients with advanced MM treated with the farnesyltransferase inhibitor R115777 (Zarnestra) in a phase 2 clinical trial. In order to enhance R115777 antitumor activity in MM, we examined the combination of this novel agent with other anticancer drugs in MM cell lines. In this study, R115777 was found to synergize with paclitaxel and docetaxel, but not with other chemotherapy agents, including doxorubicin, 5-fluorouracil, cisplastin, melphalan, mitoxantrone, and dexamethasone. R115777 synergized with paclitaxel to inhibit MM cell proliferation and to induce apoptosis. Synergism in the induction of apoptosis was accompanied by increase in cytochrome c release and caspase-3 activation. Furthermore, flow cytometry analysis also showed that paclitaxel and R115777 synergized to induce G2/M cell-cycle arrest. Importantly, synergism was observed in taxane- and R115777-resistant MM cells. In the human severe combined immunodeficient (SCID-hu) bone model of myeloma growth, the ability of paclitaxel to inhibit tumor growth in vivo was enhanced by R115777. Combination of paclitaxel or docetaxel with R115777 in the treatment of MM cells from patients with multiple myeloma was more beneficial than treatment with single agents. Our results provide the basis for combination therapy clinical trials with paclitaxel or docetaxel with R115777 in MM patients. (Blood. 2005;105:4759-4766) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Nefedova, D. M. Sullivan, S. C. Bolick, W. S. Dalton, and D. I. Gabrilovich Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy Blood, February 15, 2008; 111(4): 2220 - 2229. [Abstract] [Full Text] [PDF] Y. Qiu, X. Liu, W. Zou, P. Yue, S. Lonial, F. R. Khuri, and S.-Y. Sun The Farnesyltransferase Inhibitor R115777 Up-regulates the Expression of Death Receptor 5 and Enhances TRAIL-Induced Apoptosis in Human Lung Cancer Cells Cancer Res., May 15, 2007; 67(10): 4973 - 4980. [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] J. Pan and S.-C. J. Yeung Recent Advances in Understanding the Antineoplastic Mechanisms of Farnesyltransferase Inhibitors Cancer Res., October 15, 2005; 65(20): 9109 - 9112. [Abstract] [Full Text] [PDF]

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