Increased sensitivity of myeloid leukemia cell lines: potential of lovastatin as bone-marrow-purging agent.
Lovastatin reduces the isoprenylation of p21ras via suppression of mevalonic acid generation. Lovastatin has been shown to reduce tumor cell proliferation in a dose-dependent manner. Here, the potential of lovastatin for purging leukemia cells from bone marrow was investigated using the myeloblastic cell lines K562 and KG-1 as a model system, derived from an erythroleukemia and an acute myelogenous leukemia, respectively. Optimal purging conditions were determined using an MTT proliferation and a leukemia colony assay. Elimination of leukemia cells was time- and dose-dependent. Depletion of K562 was 2.5 logs for 100 microM of lovastatin at 72 h of incubation. Compared to another purging agent, 100 microg/ml mafosfamide had an activity comparable to 100 mM lovastatin. Interestingly, KG-1 acute myelogenous leukemia cells were even more sensitive to lovastatin than K562 cells. In clonogenic assays, 100 microM of lovastatin resulted in a 3- to 4-log reduction of K562 colonies. Lovastatin had a progressive effect on normal hematopoietic progenitor cells. At a concentration of 100 microM of lovastatin, CFU-GM colonies were reduced by 1-2 logs. In conclusion, a differential effect on leukemia and normal progenitor cells could be detected in a clonogenic assay. These results suggest that lovastatin deserves further study as an agent for ex vivo marrow purging.
Scheffold
C
C
Bone Marrow Transplantation Program, Stanford University Medical Center, Stanford, Calif., USA.
Schöttker
B
B
Lefterova
P
P
Csipai
M
M
Glasmacher
A
A
Huhn
D
D
Neubauer
A
A
Schmidt-Wolf
I G
IG
D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D016465:Bone Marrow Purging / Q000379:methods; D016026:Bone Marrow Transplantation / Q000379:methods / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006131:Growth Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020014:K562 Cells / Q000187:drug effects* / Q000473:pathology; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000473:pathology / Q000628:therapy; D008148:Lovastatin; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D014182:Transplantation, Autologous
D006131:Growth Inhibitors; D008148:Lovastatin