INHIBITORY EFFECT OF SIMVASTATIN ON THE PROLIFERATION OF HUMAN MYELOID-LEUKEMIA CELLS IN SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE

SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3-hydroxy- 3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin . by subcutaneous continuous infusion, The effect of the drug was meas ured by subsequent colony formation of surviving HL60 cells in vitro a nd flow cytometry., The number elf clonogenic HL60 cells was reduced i n the bone marrow of mice that received simvastatin compared with cont rol mice by 65% and 68% in two separate experiments. The number of clo nogenic, normal, murine, bone marrow progenitor cells concomitantly ex posed to simvastatin in vivo, was not affected in either experiment. F low cytometric analysis of bone marrow and spleen cells confirmed thes e results by showing that simvastatin had reduced the percentage of hu man leukaemia cells in these tissues by 70% and 88% respectively. The data show that the reported selective effect of simvastatin against ac ute myeloid leukaemia cells in vitro. can be extended to this ill vivo model, HL60 bears an N-ras mutation. In further in vitro studies, ket oconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyro phosphate synthesis, had a similar effect to simvastatin on HL60 colon y development. Furthermore, the clonogenicity of a population of N-ras mutated, primary acute myeloid leukaemia (AML) cells was no more sens itive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin m ay be independent of the RAS signalling pathway.