In vitro cross-resistance to nucleoside analogues and inhibitors of topoisomerase 1 and 2 in acute myeloid leukemia.
Only about one third of all patients with acute myeloid leukemia (AML) will be cured by common chemotherapy regimens. Susceptibility towards chemotherapy either of the leukemic bulk or the leukemic stem cell is considered the major determining parameter for long-term outcome. The purpose of the present study was to investigate whether chemoresistance was correlated between different antileukemic drugs or not. We determined the lethal concentration of chemotherapy necessary to reduce viability of cells to 50% compared to untreated control (LC50) as a surrogate marker of chemotherapy susceptibility of six established chemotherapeutic agents [cytarabine (median 0.83 microg/ml), daunorubicine (0.09 microg/ml), idarubicine (0.03 microg/ml), mitoxantrone (0.05 microg/ml), etoposide (4.81 microg/ml), and topotecan (0.14 microg/ml)] in an overall number of 147 samples from consecutive patients with AML by WST-1 assay in vitro. We found that susceptibility to chemotherapy was significantly correlated between all six agents (all p values < 0.01). A homogenous response of the blast populations was significantly correlated to high chemoresistance. These data indicate that cross-resistance in AML against antileukemic drugs exists between agents with different modes of action and seems not to be mediated by drug-specific resistance mechanisms but rather by more generalized death-defying features of the affected cells (e.g., inhibited apoptosis).
Fiegl
Michael
M
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
Zimmermann
Inka
I
Lorenz
Isolde
I
Hiddemann
Wolfgang
W
Braess
Jan
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009705:Nucleosides; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II