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Simvastatin impairs mitogen‐induced proliferation of malignant B‐lymphocytes from humans— in vitro and in vivo studies
Author(s) -
Vitols S.,
Angelin B.,
Juliusson G.
Publication year - 1997
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-997-0032-1
Subject(s) - simvastatin , lovastatin , hmg coa reductase , pravastatin , in vivo , medicine , chronic lymphocytic leukemia , cholesterol , hydroxymethylglutaryl coa reductase , endocrinology , lipoprotein , leukemia , lymphocyte , reductase , biology , biochemistry , enzyme , microbiology and biotechnology
Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis for their proliferation. We studied the effects of competitive inhibitors of HMG‐CoA reductase on malignant lymphocyte proliferation in vitro and in vivo . Tumor B‐cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B‐cell lymphoma were cultured for 4 d in the presence of B‐cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration‐dependent manner, the mitogen‐induced cellular thymidin uptake in medium with 10% human AB‐serum or lipoprotein‐deficient serum. Pravastatin was active only in medium with lipoprotein‐deficient serum. Ten previously untrated patients with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9–46%) and 37% (range 16–63%), respectively. Cells from four patients showed moderate to minor increases in the degradation rate of 125 I‐LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG‐CoA reductase activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during medication. However, four of the ten patients developed a therapy‐demanding progressive disease during the subsequent year. Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted.