The sensitivity of leukemic bone marrow to simvastatin is lost at remission: a potential purging agent for autologous bone marrow transplantation.
BACKGROUND
Autologous bone marrow transplantation (ABMT) is frequently used in the treatment of malignant disease but carries the risk of reintroducing tumor cells into the patient. Methods are required for removing malignant cells from harvested bone marrow (BM) without impairing hematopoietic reconstitution. We have shown that simvastatin is toxic to leukemic progenitor cells at a concentration that conserves normal BM progenitors and may be of use clinically as a novel BM purging agent.


METHODS
A two-stage culture system was used to compare the effects of simvastatin on both normal BM progenitor and primary acute myeloid leukemia (AML) cells. AML cells and normal BM mononuclear cells were incubated for 18 hours in suspension culture with 10 micrograms per mL simvastatin and the numbers of surviving clonogenic progenitor cells assayed in semisolid agar culture.


RESULTS
Following simvastatin treatment of 18 AML cell populations, the mean surviving fraction of progenitor cells was 21.3 +/- 4.8% ( +/- standard error of the mean [SEM]). In contrast, the mean survival of normal BM progenitors from 16 donors was 89.6 +/- 8.6% ( +/- SEM). Samples were taken from 6 AML patients before treatment and after remission of disease had been induced by chemotherapy. In 5 of these cases the AML sample was significantly more sensitive to simvastatin than the remission sample, 4 of the 5 showed > 80% difference in progenitor cell survival.


CONCLUSIONS
AML progenitor cells are sensitive to a short-term exposure to simvastatin that spares normal BM hematopoietic progenitor cells. We conclude that simvastatin may be an effective in vitro purging agent in ABMT for AML.
Newman
A
A
Section of Academic Haematology, Sutton, Surrey, England.
Clutterbuck
R D
RD
DeLord
C
C
Powles
R L
RL
Catovsky
D
D
Millar
J L
JL
D000208:Acute Disease; D001853:Bone Marrow / Q000187:drug effects*; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation / Q000379:methods*; D016923:Cell Death; D002478:Cells, Cultured; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012074:Remission Induction; D019821:Simvastatin; D014182:Transplantation, Autologous
D008148:Lovastatin; D019821:Simvastatin