Topoisomerase IIalpha mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia.
The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.
Uggla
Bertil
B
Department of Medicine, Orebro University Hospital, 701 85 Orebro, Sweden. bertil.uggla@orebroll.se
Tina
Elisabet
E
Nahi
Hareth
H
Paul
Christer
C
Höglund
Martin
M
Sirsjö
Allan
A
Tidefelt
Ulf
U
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001773:Blood Cells / Q000187:drug effects / Q000201:enzymology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003630:Daunorubicin; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin