title: Flow cytometry-based assessment of mitoxantrone efflux from leukemic blasts varies with response to induction chemotherapy in acute myeloid leukemia.
abstract: BACKGROUND
  Accurate prediction of chemotherapy drug resistance would aid treatment decisions in acute myeloid leukemia (AML). The aim of this study was to determine if mitoxantrone efflux from AML blasts would correlate with response to induction chemotherapy.
  
  
  METHODS
  Flow cytometry was used to measure the median fluorescence intensity (MFI) for AML blasts incubated with mitoxantrone [an ATP-binding cassette (ABC) transporter substrate] with or without coincubation with cyclosporine A (a broad-spectrum inhibitor of ABC transporters) and a ratio (MFIR) between the inhibited and uninhibited MFI was calculated.
  
  
  RESULTS
  Among 174 AML patient blast samples, the mean MFIR for complete remission (CR) patients was lower than that obtained for induction failure (IF) patients (mean MFIR ± SD 1.62 ± 0.53 for CR after one cycle of chemotherapy vs. 2.22 ± 1.29 for CR after two cycles and 2.59 ± 0.98 for IF, P < 0.001). Logistic regression analysis determined 2.45 as the MFIR threshold above which 29% of patients achieved CR vs. a CR rate of 84% when the MFIR was ≤ 2.45 (P < 0.0001). In AML patients with normal karyotype (n = 80), CR was obtained for 33% of patients with an MFIR > 2.45 vs. 89% of those with MFIR ≤ 2.45 (P < 0.0001). In patients > age 60 (n = 77), 30% vs. 87% of those with MFIR > vs. ≤ 2.45 achieved CR (P < 0.0001).
  
  
  CONCLUSIONS
  This assay of ABC transporter function can potentially predict response to induction chemotherapy in AML.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Hyun Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Lea
authors.initials: L
authors.lastname: Bernard
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berkowitz
authors.forename: Janet
authors.initials: J
authors.lastname: Nitta
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hogge
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016572:Cyclosporine / Q000494:pharmacology; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D060828:Induction Chemotherapy; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D054503:Lymphoid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D003561:Cytarabine; D016572:Cyclosporine; D008942:Mitoxantrone; D003630:Daunorubicin