Cholesterol Research Today is a free monthly online journal that collates and summarizes the latest research about Cholesterol, including details on high cholesterol, hdl, ldl, diet, risks.

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.

Kornblau SM, Banker DE, Stirewalt D, Shen D, Lemker E, Verstovsek S, Estrov Z, Faderl S, Cortes J, Beran M, Jackson CE, Chen W, Estey E, Appelbaum FR

Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston 77030-4009, USA. skornbla@mdanderson.org

Following exposure to cytotoxic agents, acute myeloid leukemia (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 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/ (M2 x day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 x 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 with 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 and 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.

Published 9 May 2007 in Blood, 109(7): 2999-3006.
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