A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors.
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and also selectively inhibits the growth of leukaemic progenitor cells. The antileukaemic action of simvastatin was compared in vitro with that of lovastatin and pravastatin, chemically related compounds which are also competitive inhibitors of HMG-CoA reductase. After 18 hours incubation with 2.5-20 microM of inhibitor, no effect was observed by any of the compounds on the subsequent clonogenic growth of normal bone marrow (BM) progenitor cells from 4 donors and BM cells from one patient in remission. However, simvastatin and lovastatin produced inhibition of acute myeloid leukaemia (AML) progenitor cell growth of between 25% and 100% in 5 populations tested (4 primary AMLs and the HL60 cell line). Pravastatin showed similar growth inhibitory effects to simvastatin and lovastatin in 2 out of 3 primary AMLs but was less active against one primary AML cell population and HL60 cells. These results indicate that, in addition to simvastatin, lovastatin and pravastatin are also selective inhibitors of leukaemic cell growth, however simvastatin was chosen for clinical trial in patients with leukaemia.
Newman
A
A
Section of Academic Haematology, Institute of Cancer Research, Sutton, Surrey, UK.
Clutterbuck
R D
RD
Powles
R L
RL
Catovsky
D
D
Millar
J L
JL
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001854:Bone Marrow Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology*; D019821:Simvastatin
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin