S. Vitols et al., SIMVASTATIN IMPAIRS MITOGEN-INDUCED PROLIFERATION OF MALIGNANT B-LYMPHOCYTES FROM HUMANS - IN-VITRO AND IN-VIVO STUDIES, Lipids, 32(3), 1997, pp. 255-262
Chronic lymphocytic leukemia (CLL) cells express lower low density lip
oprotein (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 thei
r proliferation., We studied the effects of competitive inhibitors of
HMG-CoA reductase on malignant lymphocyte proliferation in vitro and i
n 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 mi
togen-induced cellular thymidin uptake in medium with 10% human AB-ser
um or lipoprotein-deficient serum. Pravastatin was active only in medi
um with lipoprotein-deficient serum. Ten previously untreated patients
with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean red
uctions in total plasma and LDL cholesterol were 30% (range 9-46%) and
37% (range 16-63%), respectively. Cells from four patients showed mod
erate to minor increases in the degradation rate of I-125-LDL suggesti
ng that the need for exogenous cholesterol had increased, three patien
ts showed an increase in HMC-CoA reductase activity, and the cells fro
m one patient showed both. There was no significant change in the clin
ical disease status during medication. However, four of the ten patien
ts developed a therapy-demanding progressive disease during the subseq
uent year. Further clinical studies with cholesterol synthesis inhibit
ors in leukemia are warranted.