Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response.
OBJECTIVE
To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment.


METHODS
Mononuclear blood cells from AML patients were isolated before (n = 20) and after anthracycline infusion (n = 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer.


RESULTS
There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 muM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n = 24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission.


CONCLUSIONS
Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.
Bogason
Alex
A
Department of Medicine, Division of Clinical Pharmacology, Karolinska Institute/Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden.
Bhuiyan
Hasanuzzaman
H
Masquelier
Michèle
M
Paul
Christer
C
Gruber
Astrid
A
Vitols
Sigurd
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003630:Daunorubicin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015255:Idarubicin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured; D055815:Young Adult
D018943:Anthracyclines; D015255:Idarubicin; D003630:Daunorubicin