title: Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Karolinska Institute/Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Bogason
authors.forename: Hasanuzzaman
authors.initials: H
authors.lastname: Bhuiyan
authors.forename: Michèle
authors.initials: M
authors.lastname: Masquelier
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Sigurd
authors.initials: S
authors.lastname: Vitols
mesh_terms: 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
chemical_list: D018943:Anthracyclines; D015255:Idarubicin; D003630:Daunorubicin