Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 93 cases of acute myeloid leukaemia (AML) the extent to which prognostic factors mirrored the in vitro cellular chemotherapy resistance (to anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as nucleoside analogue cytarabine (Ara-C)) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. We found that age at presentation and presence of secondary AML were significantly correlated to leukaemia cell Ara-C resistance. Thus, analysis of in vitro drug resistance data revealed that age at presentation and presence of secondary leukaemia were both independently correlated to cellular drug resistance, with older age being associated with higher Ara-C resistance in vitro (p=0.02 and 0.01 in univariate and multivariate analyses, respectively) and with secondary leukaemia being associated with higher Ara-C resistance (p=0.04 and 0.059 in univariate and multivariate analysis, respectively). Median LC-50 values (Ara-C) were: 178 ng/ml in paediatric cases, 356 ng/ml in younger adult cases, and 584 ng/ml in elderly (age > or = 60 yr) cases giving a resistance ratio between these age subgroups of 1:2.0:3.3. Median LC-50 values (Ara-C) was 381 ng/ml in de novo cases as opposed to 891 ng/ml (resistance ratio 1:2.3) in secondary cases. By contrast, cytogenetic findings, presenting leucocyte count, FAB-subtype, and gender were not consistently correlated to in vitro drug resistance to any of the three drugs. We conclude that at least two major adverse prognostic factors in AML (advanced age at presentation and presence of secondary leukaemia) are associated with increased leukaemia cell Ara-C resistance. High leucocyte count is not associated with increased cellular drug resistance towards Acla, Ara-C or Dau.
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PMID:Leukaemia cell drug resistance and prognostic factors in AML. 1053 Apr 9

Inherent resistance of myeloblasts to vincristine (VCR) has been related to the activity of myeloperoxidase (MPO) which can degrade VCR in the presence of hydrogen peroxide (H2O2). We investigated the relationship between VCR degradation and hypochlorous acid (HOCl) generation from the reaction of H2O2 with chlorine (Cl) as catalyzed by MPO. A cell-free system, three human leukemia cell lines (CEM/CCRF, HL-60, U937) and 15 bone marrow samples from children with acute myeloid leukemia (AML) were studied. VCR cytotoxicity was evaluated by MTT assay and by quantitative measurement of apoptosis. In vitro levels of VCR in cell-free systems were measured by high performance liquid chromatography (HPLC), and intracellular HOCl levels by oxidation of 5-thio-2-nitrobenzoic acid with the accompanying decrease in the absorbency at 412 nm. VCR was degraded by increasing concentrations of HOCl in cell-free systems and this activity was inhibited by taurine, which is known to block HOCl activity. This finding was confirmed by the VCR cytotoxicity studies on cell lines. The HOCl-producing myeloblasts from patients were resistant to VCR. In five samples out of eight HOCl was also detected extracellularly. These results suggest that oxidation by HOCl may be the final step in VCR degradation catalyzed by MPO through its action on intracellular H2O2 and Cl. Leukemia (2000) 14, 47-51.
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PMID:Further elucidation of mechanism of resistance to vincristine in myeloid cells: role of hypochlorous acid in degradation of vincristine by myeloperoxidase. 1063 76

The ratio of Bcl-2 to Bax (Bcl-2/Bax) in 40 patients with acute myelogenous leukemia (AML) were determined. At the same time, the CFU-L of AML patients and drug resistance were detected by cell culture and MTT assay. The results showed that Bcl-2/Bax in AML was significantly higher than that in normal control (P < 0.001). Bcl-2/Bax ratio in colony growth group was higher than that in no-growth group (P < 0.05). Between drug resistance group and drug sensitivity group there was a significant difference in Bcl-2/Bax ratio (P < 0.05). There were more cases of drug resistance in high ratio group (H) than in low ratio group (L) (P < 0.05). Meanwhile, Complete Remission(CR) rate in group H was obviously lower than that in group L (P < 0.05) and patients in group H tended to have poor response. The above results indicated that the alteration of Bcl-2 and Bax is an important mechanism in the pathogenesis, progress and the development of drug resistance in AML. The determination of Bcl-2/Bax ratio has far-reaching implication in the treatment, choice of chemotherapeutic agents, and prediction of prognosis.
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PMID:Study on the relationship between the Bcl-2/Bax ratio and the growth types of leukemic cells and drug resistance in acute myelogenous leukemia. 1080 35

MTT analysis has yielded data on the sensitivity of leukemia cells isolated from 64 patients with acute leukemia to the cytokines G-KSF?, GM-KSF, interferon-alpha 2b and their combined use with drugs, such as cytosar, vepeside, doxorubicin, vincrastine, L-asparaginase. The mean in vitro survival of leukemia cells in children with acute lymphoblast cell leukemia (ALCL) was 1.9 times less than that in acute myeloblast cell leukemia (AMCL) (p < 0.001), that in new cases of ALL was 2.3 times less than in relapses (p = 0.024). The stimulating effect of GM-KSF on the survival rates of leukemia cells was seen in 64.7% of patients with AML. That of GM-KSF was recorded in 21.4% of cases. The survival of lymphoblast cells isolated from children with ALL did not differ greatly in the absolute majority of cases (by more than 30%) in the presence of growth factor in the medium. The cytotoxicity of XII with medium growth factor decreased in most cases. However, some cases (more frequently in AML than ALCL) displayed a higher cytotoxicity of XII, particularly cytosar in the presence of G-KSF and GM-KSFG; LC50 of Ara-C decreased by 30% or more in the presence of growth factor in 36% of patients. Incubation with interferon alpha 2b caused a reduction in the survival of leukemia cells, which was more pronounced in children with ALL. Interferon-alpha 2b caused an increase in the cytotoxic effect of XII on leukemia cells in ALL to a greater extent; cytosar, vepeside, and doxorubicin enhanced the effect by 1.47, 1.39, and 2.35 times, respectively.
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PMID:[Study of tumor cells sensitivity in patients with acute leukemia to cytokines and their combined use with drugs in vitro by MTT analysis]. 1094 55

Lovastatin reduces the isoprenylation of p21ras via suppression of mevalonic acid generation. Lovastatin has been shown to reduce tumor cell proliferation in a dose-dependent manner. Here, the potential of lovastatin for purging leukemia cells from bone marrow was investigated using the myeloblastic cell lines K562 and KG-1 as a model system, derived from an erythroleukemia and an acute myelogenous leukemia, respectively. Optimal purging conditions were determined using an MTT proliferation and a leukemia colony assay. Elimination of leukemia cells was time- and dose-dependent. Depletion of K562 was 2.5 logs for 100 microM of lovastatin at 72 h of incubation. Compared to another purging agent, 100 microg/ml mafosfamide had an activity comparable to 100 mM lovastatin. Interestingly, KG-1 acute myelogenous leukemia cells were even more sensitive to lovastatin than K562 cells. In clonogenic assays, 100 microM of lovastatin resulted in a 3- to 4-log reduction of K562 colonies. Lovastatin had a progressive effect on normal hematopoietic progenitor cells. At a concentration of 100 microM of lovastatin, CFU-GM colonies were reduced by 1-2 logs. In conclusion, a differential effect on leukemia and normal progenitor cells could be detected in a clonogenic assay. These results suggest that lovastatin deserves further study as an agent for ex vivo marrow purging.
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PMID:Increased sensitivity of myeloid leukemia cell lines: potential of lovastatin as bone-marrow-purging agent. 1115 78

Treatment failure in AML is often attributed to P-glycoprotein-associated multidrug resistance. However, the importance of increased DNA repair in resistant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we continually exposed blasts cells, isolated from 22 patients with AML, to a variety of agents +/- 15 microM aphidicolin for 48 hours. Cell survival was measured using the MTT assay. Overall, there was no significant effect of aphidicolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabine. However, there was a marked increase in sensitivity to ara-C with a median 4.75-fold increase overall (range 0.8-80-fold;P< 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vitro to ara-C (8.9-fold compared to 2.12-fold, P< 0.01). This observation was further validated by the correlation between ara-C LC(50)and extent of modulation effect (P< 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC(50)normal cells/tumour cells) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity without increased haematotoxicity makes the combination of ara-C plus aphidicolin ideal for inclusion in future clinical trials.
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PMID:Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML. 1123 90

In 85 adult patients diagnosed with acute myeloid leukaemia (AML) and treated at the same institution during a 5-yr period, the clinical significance of in vitro cellular drug resistance to the anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as the nucleoside analogue cytarabine (Ara-C) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. In 59 patients of whom 40 were treated by the combination of Acla and Ara-C we found that leukaemia cell drug resistance towards Acla was higher (by a factor 2.80) in patients who failed to enter complete remission (CR) after the first cycle of induction chemotherapy as compared to patients who entered complete remission. The relationship was significant in univariate as well as multivariate analysis (p=0.02 and 0.03, respectively). By contrast, no in vitro single drug resistance values were consistently correlated to other parameters of clinical outcome (overall CR rate, overall survival (OS), or continuous complete remission (CCR)), whereas the combined Acla and Ara-C drug resistance profile (Acla/Ara-C DRP) was of prognostic significance to overall survival of all 85 patients (p=0.004) as well as to the CCR of 39 complete responders (p=0.04). These findings remained statistically significant in multivariate analyses correcting for other variables influencing clinical outcome including patient age, leukocyte count, karyotype, FAB-subtype, and presence/absence of secondary AML. We conclude that the in vitro drug resistance of leukaemia cells at time of disease presentation appears to be independent of prognostic significance to short- and long-term clinical outcome in AML.
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PMID:Pretreatment leukaemia cell drug resistance is correlated to clinical outcome in acute myeloid leukaemia. 1135 Apr 84

Anthracyclines have been the backbone of acute leukemia therapy in the adult for many years, but little attention has been paid to the long-term toxicity of these agents in this disease because of the poor survival of this population of patients. Recent studies have examined dose-intensified daunorubicin with dosages as high as 95 mg/m2 daily x 3 in this population with the attendant concerns of both acute and chronic toxicity. We have examined three human leukemia cell lines in vitro, treated with either daunorubicin, mitoxantrone, with or without cytosine arabinoside in the presence of dexrazoxane to determine whether such treatment would be synergistic or antagonistic. AML-193, CRF-SB, and Molt-4 cell lines were grown to confluence, plated into microtiter dishes and incubated for 72 h with varying concentrations of the above drugs. Cytotoxicity was determined by the MTT assay, and synergy or antagonism by median effect analysis. Dexrazoxane demonstrated additive or synergistic cytotoxic effects (CI <1) under most conditions. The triplet of daunorubicin, cytosine arabinoside, and dexrazoxane showed profound synergy in all three cell lines. These effects occurred at clinically achievable levels. If high dosages of anthracyclines are contemplated in this population, these preclinical data suggest that the addition of dexrazoxane to classical therapy is not antagonistic and thus may allow an investigation of the role of dexrazoxane as a cardiac protectant.
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PMID:In vitro effects of dexrazoxane (Zinecard) and classical acute leukemia therapy: time to consider expanded clinical trials? 1158 8

To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French-American-British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.
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PMID:Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia. 1175 10

It has been proposed that flavonoids may have potential as anticancer agents. In this study, we showed that tartary buckwheat flavonoid (TBF) obviously inhibits the growth of human acute myelogenous leukemia (AML) HL-60 cells by MTT assay. The inhibitory effect of TBF on the proliferation of HL-60 cells is related to the induction of apoptosis, which is confirmed by DNA ladder formation on gel electrophoresis and apoptosis morphological changes under light microscope. Furthermore, HL-60 cells undergo rapid apoptosis upon treatment with TBF, as indicated by increased annexin V binding capacity and caspase 3 activation with flow cytometric analysis. Thus, our data provide a potential mechanism for the chemopreventive activity of tartary buckwheat flavonoid and suggest that it may have a potentially therapeutic role for human leukemia.
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PMID:Tartary buckwheat flavonoid activates caspase 3 and induces HL-60 cell apoptosis. 1183 16


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