SEARCH:   Advanced

Blood, 14 May 2009, Vol. 113, No. 20, pp. 4841-4852. Prepublished online as a Blood First Edition Paper on December 24, 2008; DOI 10.1182/blood-2008-08-172726. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-08-172726v1 113/20/4841    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 Karp, J. E Articles by Kaufmann, S. H. Search for Related Content PubMed PubMed Citation Articles by Karp, J. E Articles by Kaufmann, S. H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 11, 2008 Accepted December 14, 2008 Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: A preclinical and phase I trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Judith E Karp*, Karen Flatten, Eric J Feldman, Jacqueline M Greer, David A. Loegering, Rebecca M. Ricklis, Lawrence E. Morris, Ellen Ritchie, B. Douglas Smith, Valerie Ironside, Timothy Talbott, Gail Roboz, Son B. Le, Xue Wei Meng, Paula A. Schneider, Nga T. Dai, Alex A. Adjei, Steven D. Gore, Mark J. Levis, John J. Wright, Elizabeth Garrett-Mayer, and Scott H. Kaufmann Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD, United States Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States Department of Hematology/Oncology, New York Presbyterian Hospital, Cornell Medical Center, New York, NY, United States Bone Marrow Transplant Group of Georgia, Atlanta, GA, United States Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, United States Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States * Corresponding author; email: jkarp2{at}jhmi.edu. The farnesyltransferase inhibitor tipifarnib (T) exhibits modest activity against acute myelogenous leukemia (AML). To build on these results, we performed experiments to examine the effect of combining T with other antileukemic agents. These studies demonstrated that tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide (E)-induced antiproliferative effects in lymphohematopoietic cell lines and AML isolates. We subsequently conducted a phase I trial of T+E in adults over age 70 who were not candidates for conventional therapy. 84 patients (median age 77) received 224 cycles of oral T (300-600 mg bid for 14 or 21 days) + oral E (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day T. Complete remissions (CR) were achieved in 16/54 (30%) receiving 14-day T vs. 5/30 (17%) receiving 21-day T. CRs occurred in 50% of two 14-day T cohorts: 3A (T 600, E 100) and 8A (T 400, E 200). In vivo, T+E decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. We conclude that T+E administered for 14 days is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered on www.clinicaltrials.gov as NCT00112853. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Tipifarnib and etoposide for older AML patients: from bench to bedside Felicetto Ferrara Blood 2009 113: 4824-4825. [Full Text] [PDF] This article has been cited by other articles: F. Ferrara Tipifarnib and etoposide for older AML patients: from bench to bedside Blood, May 14, 2009; 113(20): 4824 - 4825. [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020