Simvastatin impairs mitogen-induced proliferation of malignant B-lymphocytes from humans--in vitro and in vivo studies.
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 untreated 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 1251-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.
Vitols
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Department of Clinical Pharmacology, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Angelin
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B
Juliusson
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G
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000473:pathology; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology; D019821:Simvastatin; D013936:Thymidine / Q000378:metabolism / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D008077:Lipoproteins, LDL; D008934:Mitogens; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin; D013936:Thymidine