Cytotoxic activity of the third-generation bisphosphonate zoledronic acid in acute myeloid leukemia.
The third-generation bisphosphonate zoledronic acid (ZOL) has recently been shown to be active against human tumour and leukemic cell lines. The purpose of this study was to evaluate the antileukemic potential of ZOL in acute myeloid leukemia (AML). We determined the lethal concentration 50% (LC 50) using the WST-1 assay of ZOL as being 287.9 microg/ml after 24 h and 108.3 microg/ml after 96 h in HL 60 cells and to be 382.4 and 43.2 microg/ml, respectively, in nine samples from patients with AML. The ZOL induced inhibition of proliferative activity of HL 60 cells could not be abrogated by the hematopetic growth factors G-CSF and GM-CSF. ZOL was found to by cytotoxic in HL 60 cells without activation of caspase 3. ZOL was not cross resistant with cytarabine as shown by the linear correlation of LC 50s. Both agents, however, exerted an additive cytotoxicity as revealed by isobologram-analysis and combination index. These data warrant further investigation of ZOL in the treatment of AML.
Fiegl
Michael
M
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, 81377 Munich, Germany.
Juergens
Matthias
M
Hiddemann
Wolfgang
W
Braess
Jan
J
D000208:Acute Disease; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004164:Diphosphonates / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D000077211:Zoledronic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053148:Caspase 3