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.

Less Utilized Prognostic Markers in Acute Myeloid Leukemia

“…High levels correlated with poor response to chemotherapy [56,57] and short duration disease free survival [56,58] . Contrasting results were obtained in another study where spontaneous proliferative determined by tritiated thymidine incorporation was significantly higher in favourable karyotypes compared to cases with unfavorable cytogenetics [59] .…”

“…Lowenberg et al [56] (1993) and our group [57] used serum free media while Norgaard et al [57] (1996) used RPMI with FCS as culture media. The results here did not correlate with FAB subgroups.…”

“…The number of CFUblast induced from AML cells depleted of T cells and stimulated with PHA-L [53,54] or by autonomous growth [54] was inversely correlated with remission induction [53,55] and duration of survival [53,54,55] . AML blasts in suspension cultures also utilized other detection methods including incorporation of tritiated thymidine incorporation [56] and methyl tetrazolium (MTT) assay [57,58] to 98 © 2016 ACT. All rights reserved.…”

“…Complete remission is achievable in 65% de novo AML and 41% secondary AML. Median overall survival for these patients was 1119 days for age 16-55 years (N=554), 350 days for age [56][57][58][59][60][61][62][63][64][65] years (N = 437) and 80 days for patients aged 76-89 year old (N = 968) [1] . The French-American-British (FAB) classification of acute myeloid leukemias, the first classification established more than 40 years ago, identifies eight subtypes (M0-M7) based on morphology and cytochemistry staining.…”

Gene expression of PROSC (proline synthetase co-transcribed) in related to cytosine arabinoside sensitivity in human leukemia

“…Ara-C is widely used to treat leukemia in humans 1) , but often becomes ineffective because of increased resistance to the exposure of ara-C and results in worse clinical prognosis 2) . Therefore, it is important to understand the mechanism responsible for the drug resistance and develop new therapies to overcome the drug resistance.…”