Inhibited apoptosis and drug resistance in acute myeloid leukaemia.
Despite extensive investigation into mechanisms of drug resistance in acute myeloid leukaemia (AML), the aetiology of therapeutic resistance is unclear. We found that five leukaemia cell lines (K562, HL-60, CEM. CEM induced to overexpress bcl-2, and REH) displayed parallel sensitivity to four antileukaemia drugs with different mechanisms of action, with K562 generally being the least sensitive and REH being the most sensitive. The amount of spontaneous apoptosis in the cell lines after serum-free culture paralleled their drug sensitivity: K562 cells displayed the least apoptosis at 24h (2.50 +/- 0.24%) and REH the most (24.47 +/- 8.22%). The extent of spontaneous apoptosis of leukaemic blasts from 39 patients with newly diagnosed de novo AML also correlated with the success of the intensive, infusional cytarabine-based induction therapy. There was a median of 19.5% (range 3.6-64%) apoptotic AML cells after 24 h of serum-free culture in patients who entered a complete remission compared with 4.2% (1.8-7.0%) apoptotic AML cells in patients who did not achieve a complete remission (P = 0.0007). Thus, inhibited apoptosis was associated with both in vitro and in vivo pan-resistance to antileukaemic chemotherapy. The cause of inhibited apoptosis in AML is probably a function of interactions among multiple signals that influence apoptosis. Assessment of spontaneous apoptosis may serve as an important prognostic factor for AML.
Smith
B D
BD
Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-8967, USA.
Bambach
B J
BJ
Vala
M S
MS
Barber
J P
JP
Enger
C
C
Brodsky
R A
RA
Burke
P J
PJ
Gore
S D
SD
Jones
R J
RJ
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology*; D008875:Middle Aged; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free