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 145 adult patients diagnosed with non-M3 acute myeloid leukaemia (AML) the relevance of FAB-subtype and immunophenotype to in vitro cellular drug resistance towards the anthracyclines aclarubicin (Acla) and daunorubicin (Dau), and the nucleoside analogue cytarabine (Ara-C), as well as other antileukaemic drugs, was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. We demonstrate that high CD14 expression is highly significantly associated with high cellular Ara-C and Dau resistance in univariate as well as multivariate analyses. FAB subtypes with highest and lowest cellular Ara-C resistance were M4 and M5, respectively (P < 0.01, one-way anova), whereas FAB subtypes with highest and lowest cellular Dau resistance were M4 and M1, respectively (P < 0.01, one-way anova). By contrast, no significant differences in cellular drug resistance towards Acla could be demonstrated among FAB subtypes. Furthermore, in two cohorts of AML patients treated by two different regimens for remission induction over a period of 15 yr (1985-94, n = 159 and 1995-99, n = 76, respectively) we demonstrate in univariate analyses a significance of CD14 expression with respect to clinical outcome. With the exception of significance to probability of obtaining complete remission in the first cohort (P = 0.03, logistic regression), this significance was, however, lost in multivariate analyses. It was demonstrated that FAB-M4 patients were older than M5 patients and that high CD14 expression was associated with the presence of secondary AML and older age. We conclude that although cases with high blast cell CD14 expression (and FAB-M4 cases) were more resistant to Ara-C as well as Dau in vitro, the clinical and biological significance of this may be debatable because of interactions with major prognostic factors in AML.
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PMID:FAB M4 and high CD14 surface expression is associated with high cellular resistance to Ara-C and daunorubicin: implications for clinical outcome in acute myeloid leukaemia. 1186 Apr 42

Dexrazoxane (DEX) prevents the formation of free radical, lipid peroxidation and cardiotoxicity caused by anthracyclines. Due to a concern about its possible interference with anthracyclin cytotoxicity, the in vitro effect of DEX on daunorubicin (DNR) cytotoxicity, cell cycle and induction of apoptosis by annexin-V was investigated. The sensitivity to DEX, DNR and their combination was tested by the MTT assay in human promyelocytic leukemia HL-60, the erythroid blast crisis CML K562 cell lines and in 45 children with ALL and AML. Cell cycle analysis and annexin-V expression were performed by flow cytometry. It has been observed that DEX itself weakly, but significantly caused cytotoxicity in both cell lines and in patient samples, especially in initial ALL samples. DEX sensitized K562 and HL60, but not patient samples, to cytotoxicity of DNR. The percentage of necrotic/apoptotic cells, as detected in cell cycle analysis and annexin V staining, was higher after exposure to DEX +/- DNR, when compared to respective samples not treated with DEX, in both cell lines but not in patient samples. Expression of annexin V induced by DEX in both cell lines was enlarged, regardless of the presence of DNR. This difference was not observed in patient samples, however, the number of cells expressing annexin V was higher after exposure to DEX +/- DNR in comparison to respective samples not treated with DEX. In conclusion, it seems that DEX possibly has no impact on the sensitivity of childhood leukemic blasts to DNR, however, has weak cytotoxic properties itself.
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PMID:Dexrazoxane has no impact on sensitivity of childhood leukemic blasts to daunorubicin. 1198 42

Glufosfamide is a new agent for cancer chemotherapy. The objective of the study was the comparison of the in vitro drug resistance profile of glufosfamide with other oxazaphosphorines in 106 samples of childhood acute leukemia by means of the MTT assay. The following drugs were tested: glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide, mafosfamide cyclohexylamine salt, prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine. In the group of initial Acute Lymphoblastic Leukemia (ALL) samples, equivalent cytotoxicity values for glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide and mafosfamide were 5.95, 9.92, 4.60 and 3.90 microg/ml, respectively. In comparison to initial ALL samples, the relative resistance for glufosfamide and 4-HOO-ifosfamide in relapsed ALL samples were 1.9 (p=0.049) and 1.3 (ns), and in initial Acute Myeloblastic Leukemia (AML) samples, respectively, 31 (p<0.001) and 5 (p=0.001). All oxazaphosphorines showed highly significant cross-resistance. In conclusion, in vitro activity of glufosfamide is comparable to ifosfamide. Glufosfamide shows high activity against lymphoblasts both on diagnosis and on relapse, however it cannot circumvent resistance to other oxazaphosphorines.
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PMID:In vitro activity of glufosfamide in childhood acute leukemia. 1201 97

Resistance to glucocorticoids is nowadays one of the strongest adverse risk factors in the treatment of childhood acute lymphoblastic leukemia (ALL). Differential in vitro antileukemic activity of various glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and myeloblastic leukemia was determined by means of the MTT assay in 49 successfully tested samples of childhood acute leukemia. The equivalent antileukemic concentrations of respective drugs against lymphoblasts in de novo ALL samples were: 35 microM of hydrocortisone; 8 microM of prednisolone; 1.6 microM of methylprednisolone; 0.47 microM of dexamethasone and 0.23 microM of betamethasone. In comparison to initial ALL samples, the group of relapsed ALL was more resistant to: prednisolone (38-fold, p=0.004), dexamethasone (>32-fold, p=0.004), methylprednisolone (37-fold, p=0.039), betamethasone (38-fold, p=0.018) and hydrocortisone (33-fold, p=0.030). The group of acute myeloid leukemia (AML) samples were resistant to: prednisolone (>83-fold, p<0.001), dexamethasone (>32-fold, p<0.004), methylprednisolone (>65-fold, p=0.003), betamethasone (>66-fold, p=0.004) and hydrocortisone (61-fold, p=0.007), when compared to ALL at presentation. A significant cross-resistance between all used glucocorticoids as well as between glucocorticoids and other tested anti-leukemic drugs was found. In some individual cases in vitro glucocorticoid cross-resistance was less pronounced and relatively good antileukemic activity of betamethasone was observed.
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PMID:In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia. 1209 4

Glufosfamide (beta-D-glucosyl-ifosfamide mustard) is a new agent for cancer chemotherapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demonstrates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from children with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n = 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8 microM, respectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines presented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse.
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PMID:In vitro activity of oxazaphosphorines in childhood acute leukemia: preliminary report. 1213 44

In vitro antileukemic activity of five glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and non-lymphoblastic leukemia were determined by means of the MTT assay in 25 leukemia cell samples of childhood acute leukemias. The equivalent antileukemic concentrations of the drugs tested were: 34 microM hydrocortisone (HC), 8 microM prednisolone (PRE), 1.5 microM methylprednisolone (MPR), 0.44 microM dexamethasone (DX) and 0.22 microM betamethasone (BET). In comparison with initial ALL cell samples, the relapsed ALL group was more resistant to PRE (38-fold, p = 0.044), DX (> 34-fold, p = 0.04), MPR (38-fold), BET (45-fold) and HC (33-fold). The AML cell samples were even more resistant to: PRE (> 85-fold, p = 0.001), DX (> 34-fold, p = 0.004), MPR (> 69-fold, p = 0.036), BET (> 69-fold, p = 0.038) and HC (54-fold, p = 0.059) when compared with ALL on initial diagnosis. A significant cross-resistance among all the glucocorticoids used was found. Only in some individual cases the cross-resistance was less pronounced.
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PMID:Cross-resistance to five glucocorticoids in childhood acute lymphoblastic and non-lymphoblastic leukemia samples tested by the MTT assay: preliminary report. 1213 61

By using CFU-GM/CFU-L colony assay, NBT/MTT reductant test and DNA fragmentation analysis, we studied the effects of Sophora flavescens (SF) on CFU-GM proliferative ratio in human normal bone marrow/umbilical cord blood and on proliferation, differentiation and apoptosis in human acute myelogenous leukemia HL-60 cells. The results showed that 5, 10, 15, 20 micrograms.microliter-1 of SF significantly inhibited proliferation and induced apoptosis in the HL-60 cells in a dose-dependent fashion. Fifteen micrograms.microliter-1 of SF also induced differentiation in HL-60 cells. Furthermore, cytotoxic activity of SF(5-15 micrograms.microliter-1) was not apparent on human normal hematopoietic progenitors(CFU-GM). The results indicate that an appropriate concentration of SF has a selective antileukemic effect. Thus, these are important impetuses for further research of SF as an anticancer agent.
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PMID:[The anti-leukemia effect of Sophora flavescens and its mechanism]. 1221 13

We have found the short-term MTT assay to be a simple, reproducible chemosensitivity technique, suitable for use throughout the time course of disease. We now have 12 years' experience of using this method in a variety of tumour types, both haematological and solid malignancies. Tumour cells are isolated from bone marrow, malignant effusions or solid biopsies and subjected to drug exposure for 48-96 h. Cell survival is measured by re-incubation in MTT for 4 h. We have found a significant correlation of in vitro results with in vivo outcome for acute myeloid leukaemia (AML) and for ovarian cancer (both p < 0.0001) with an assay sensitivity of 98% for AML and 81% for ovarian cancer. Furthermore, the 5-year survival of ovarian cancer patients treated with a drug found sensitive in vitro is significantly higher than that for patients treated with a drug found resistant in vitro (p = 0.033). We have correlated assay results with drug resistance markers. For example, expression of the newly described half transporter BCRP is related to daunorubicin resistance (p < 0.05). The MTT assay is also suitable for screening for modulation of drug resistance. We have found that the DNA polymerase inhibitor aphidicolin markedly increases in vitro sensitivity to the platinum drugs in ovarian cancer and cytosine arabinoside in AML in the majority of patients. The greatest effect was seen for patients deemed resistant in vitro to these agents. We have identified novel drug combinations which demonstrate significant synergism using this methodology and have also used it to study the emergence of drug resistance in cell line models with a view to its prevention. In conclusion, we have found the MTT assay to be a simple, repeatable, adaptable technique which produces accurate information to help the clinician select suitable treatment for individual cases.
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PMID:The use of the MTT assay to study drug resistance in fresh tumour samples. 1252 95

Cellular drug resistance is an important determinant of the response to chemotherapy, and its precise measurement may have clinical relevance. Potential applications are: prognostic factor for risk-group stratification, tailored chemotherapy for subgroups or individual patients with a specific cellular drug resistance profile, determination of cross-resistance patterns, study of drug interactions, study of resistance modulation or circumvention, selection of patients for phase II studies and screening for the cytotoxicity of novel compounds. The colorimetric 4-day MTT assay is a frequently used method. However, a distinction between malignant and non-malignant cells cannot be made, which should be taken into account. In the case of a relatively high percentage of contaminating non-malignant cells, the differential staining cytotoxicity (DiSC) assay can be used. The MTT assay's technical success percentage is about 80% for fresh ALL and AML samples. For methotrexate (MTX) a different assay must be used, such as the thymidylate synthase inhibition assay (TSIA). The MTT assay measures the number of living cells that survived drug exposure. Therefore, the effect of many if not most drugs to induce leukemia cell death by apoptosis is also included. This review mainly summarizes the data on cellular drug resistance in childhood leukemia, as obtained by the MTT assay and TSIA, in our laboratory in Amsterdam. These data clearly demonstrate the significant relation between in vitro cellular drug resistance and clinical and cell biological features and short- and long-term clinical outcome in childhood leukemia. In conclusion, cellular drug resistance testing provides clinically relevant information that can be available within 1 week and can be performed successfully in the vast majority of leukemia samples. The data are more and more being used and being considered for use in clinical trials in leukemia.
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PMID:Clinical significance of cellular drug resistance in childhood leukemia. 1252 9

A method for evaluating the regrowth drug resistance in relapsed acute myelogenous leukemia (AML) was developed. Drug sensitivity and proliferation of leukemic cells in vitro were determined using leukemic cell colony forming unit (CUF-L), MTT drug-sensitive test, percentage of S phase cells in cell cycle (S%), fluorescent index (FI) and drug resistant index (DRI) by detecting intracellular daunorubicin, expression of P-170 glycoprotein by APAAP assay, and abundance of Bcl-XL mRNA by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) methods. First, the correlation between scoring criteria and cell drug resistance and cell proliferation was investigated in newly untreated AML patients. Second, 20 patients with relapsed AML were marked. According to each tested result, its point(s) was scored. The results showed that among the 20 cases of relapsed AML, 9 were diagnosed as having regrowth drug resistance. It was concluded that the scoring method for regrowth drug resistance was first developed in AML. There was regrowth drug resistance in relapsed AML; clinically circumventing it would be of extreme significance for establishment of new approaches to the treatment in AML.
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PMID:Investigation on marking method for phenomenon on regrowth drug resistance in relapsed acute myelogenous leukemia. 1253 49


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