title: Relation of blast cell survival and proliferation to chemotherapy resistance in AML.
abstract: We have investigated the in vitro blast cell survival (viability) and drug resistance to cytosine arabinoside (Ara-C), daunorubicin (Dau), mitoxantrone (Mitox) and aclarubicin (Acla) of fresh leukaemic blast cells from 80 patients with newly diagnosed acute myeloid leukaemia (AML) employing the semiautomated colourimetric MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)-assay. In 15 cases we concurrently investigated the relation between in vitro blast cell survival (MTT assay) and blast cell proliferation (3H-thymidine incorporation) in the presence and absence of myeloid growth factors (GFs) G-CSF, GM-CSF and IL-3 (individually and in combination). A highly significant correlation was found between blast cell survival and blast cell proliferation (r = 0.87, P < 1 x 10(-4). Furthermore, in 40 evaluable adult patients who completed intravenous induction chemotherapy and were evaluable for response to chemotherapy we found a positive correlation between in vitro blast survival (MTT assay) and response to chemotherapy with high blast survival being associated with poor response to chemotherapy (P = 0.05). Moreover, in a multivariate analysis, high blast cell survival was significantly associated with high CD13 expression and monocytic phenotype (P = 0.0003 and P = 0.02, respectively). Furthermore, we found an inverse relationship between the baseline proliferation of the blasts and the magnitude of response to the GFs (P < 0.02), indicating that cells with low baseline proliferation were more readily stimulated by growth factors. Finally, we found a significant correlation between leukaemic cell survival and cellular drug resistance towards Dau (P = 0.001) and Mitox (P = 0.03), but not towards Ara-C (P = 0.68) and Acla (P = 0.13). We conclude that high in vitro leukaemic cell survival is associated with drug resistance in vivo and in vitro, and furthermore is correlated with high blast cell proliferation and some adverse prognostic factors previously identified in AML.
authors.affiliation: Department of Medicine and Haematology, Danish Cancer Society, Aarhus, Denmark.
authors.forename: J M
authors.initials: JM
authors.lastname: Nørgaard
authors.forename: S T
authors.initials: ST
authors.lastname: Langkjer
authors.forename: T
authors.initials: T
authors.lastname: Palshof
authors.forename: N
authors.initials: N
authors.lastname: Clausen
authors.forename: B
authors.initials: B
authors.lastname: Pedersen
authors.forename: P
authors.initials: P
authors.lastname: Hokland
mesh_terms: D015250:Aclarubicin / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000627:therapeutic use*; D003630:Daunorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D015250:Aclarubicin; D008942:Mitoxantrone; D003630:Daunorubicin