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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2999-3006. Prepublished online as a Blood First Edition Paper on December 7, 2006; DOI 10.1182/blood-2006-08-044446. This Article Full Text (PDF) Supplemental Table All Versions of this Article: blood-2006-08-044446v1 109/7/2999    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 Kornblau, S. M. Articles by Appelbaum, F. R Search for Related Content PubMed PubMed Citation Articles by Kornblau, S. M. Articles by Appelbaum, F. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 31, 2006 Accepted November 20, 2006 Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high dose Ara-C: A Phase 1 study Steven M. Kornblau*, Deborah E. Banker, Derek Stirewalt, Danny Shen, Elizabeth Lemker, Srdan Verstovsek, Zeev Estrov, Stefan Faderl, Jorge Cortes, Miloslav Beran, C. Ellen Jackson, Wenjing Chen, Elihu Estey, and Frederick R Appelbaum Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Seattle, WA Fred Hutchinson Cancer Research Center, Seattle, WA Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Seattle, WA * Corresponding author; email: skornblau{at}mdanderson.org. Following exposure to cytotoxic agents, AML blasts elevate cellular cholesterol, in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase I study evaluated adding pravastatin (PV) (40-1680 mg/day days 1-8), to idarubicin (ida)(12 mg/M2/d, days 4-6) + high-dose cytarabine (HDAC) (1.5 g/M2/day by CI, days 4-7) in 15 newly diagnosed and 22 salvage patients with unfavorable (n=26) or intermediate (n=10) prognosis cytogenetics. Compared to historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride, total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV+Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Sassano, M. Lo Iacono, G. Antico, A. Jordan, S. Uddin, R. A. Calogero, and L. C. Platanias Regulation of leukemic cell differentiation and retinoid-induced gene expression by statins Mol. Cancer Ther., March 1, 2009; 8(3): 615 - 625. [Abstract] [Full Text] [PDF]

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