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

Drug resistance is one of the most significant impediments in the treatment of hematological malignancies. There have been a number of studies on the incidence of P-GP expression in tumor cells or tissues, where detectable level of P-GP has been found in all types of hematological malignancies. P-GP expression and significance in the patients varies widely between reported studies on patients with different ages and different disease types. Some of this validation can be accounted for by the threshold used to consider a sample positive for P-GP. However, mdr-1 is likely important in determining therapeutic outcome in patients with AML, NHL, and MM, although there is a suggestion of a different "behavior" between adult and childhood AML. In contrast, the significant prognostic association with expression of MRP and LRP is not consistent with disease types and disease stages. Clinical trials of modulation of MDR have been limited by following major factors. One is inability of achieving adequate blood levels of the modulator to reverse MDR, and the other is presence of other resistance mechanisms in addition to P-GP. The fact that P-GP modulators alter the pharmacokinetics of anti-cancer drugs can potentially increase toxicities if the dose of anticancer drugs is not appropriately reduced. Recently, MDR modulators such as valspodar have demonstrated substantial inhibition of P-GP. In this presentation, a number of characteristics in VCR-resistant cells are reported. We demonstrate that acquisition of MDR or recovery from MDR phenotypes differ in one cell type to another, a marked correlation between P-GP and susuceptibility to oxygen radicals, and altered gene expression of cell membrane antigen and apoptosis cascade genes. The efficacy of immunotherapies depends on the altered or unchanged target molecules of MDR cells. Thus, immunotherapies or reversal agents that aim at these substances in tumor cells should be useful to overcome MDR phenotypes.
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PMID:Biology and modulation of multidrug resistance (MDR) in hematological malignancies. 1243 Sep 27

The failure to chemotherapy is a multi factorial phenomenon and lung resistance protein (LRP) overexpression has already been discussed as implicated in drug resistance. But its role is still discussed. In 1996, we studied the expression of LRP and P170 (MDR) in a series of leukemias, at the time of diagnosis, by immunocytochemical (ICC) method. The observation of a strong and unusual expression of LRP in acute myeloid leukemia (AML) with monocytic component led us to test (for P170 and LRP) a new series of 47 AML with different FAB subtypes. The expression of LRP was scored from 1 to 5 in blast cells and monocytes separately. We demonstrate that LRP is not correlated with clinical outcome but is statistically related to monoblastic leukemias. Code 5 reaction was found in 10/13 M5 versus the other FAB subtypes (P<10(-3)). The strongest LRP overexpression was also found in chronic myelomonocytic leukemia (four cases), reactive monocytosis (three cases) and in a dendritic cell line. In conclusion, we report that LRP is rather a marker of monocytic lineage than a prognostic index for MDR and we suggest that detection of LRP by ICC could be an argument for the diagnosis of monoblastic and monocytic leukemias.
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PMID:LRP overexpression in monocytic lineage. 1280 35

The biological activity of MEN 11079, a new daunorubucin analogue with a fluorine atom in C(8) of ring A, was investigated in the human leukemic cell lines K-562 and in mononuclear cells (MNCs) of 40 patients with acute myeloid leukemia (AML) and the activity compared to two well-characterized anthracyclines, idarubicin (IDA) and doxorubicin (DOXO). IDA and MEN 11079 were more active than DOXO in cytotoxicity tests (WST-1 assay). IDA and MEN 11079 ID(50) values were also significantly different from each other (K-562: P=0.038; MNCs: P=0.003). Moreover, the range was 0.002-4.300 microM for IDA and 0.002-0.670 microM for MEN 11079, in the MNCs. Therefore, the latter appeared to assure a smaller variability of response in the AML cells. Apoptosis assays (performed using Annexin-V assay and propidium iodide) and cell cycle studies demonstrated that the MEN 11079 effective concentration was 10-fold lower than the DOXO and IDA ones. MDR (Pgp and MRP1 proteins), as measured by semiquantitative RT-PCR, cytofluorimetric and functional analysis of proteins, was similarly elicited by IDA and MEN 11079. In conclusion, the response of the cells to the new anthracycline indicates that there is greater cytotoxic activity of this molecule than IDA and DOXO. Its narrower ID(50) range may allow for a more predictable response in the clinical setting.
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PMID:In vitro antileukemic effect of a new anthracycline analogue, MEN 11079. 1292 51

The recent treatment of hematological malignancies appears to be unsatisfactory in child and adult patients with acute myeloid leukemia and adult patients with acute lymphocytic leukemia. A major problem in the treatment of leukemia is caused by the development of drug resistance to chemotherapeutic agents, which is already present at diagnosis or after chemotherapy as a minimal residual disease, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemia clone. It was suggested that the mechanisms of drug resistance consist of drug resistance proteins, which work as a drug efflux pump. These are the permeability-related glycoprotein (P-Gp), the multidrug-resistance associated protein (MRP), the lung resistance protein (LRP), and other MDR proteins such as the transporter associated with antigen processing (TAP), anthracyclin resistance associated protein (ARA), MRP 2-7, and breast cancer resistance protein (BCRP). In addition, anti-apoptosis mechanisms, alterations of tumor suppressor genes, altered immunogenicity, drug resistance mechanisms for individual drugs, and clinical risk factors such as white blood cell count, age, and other factors have been reported to act in drug resistance singly or in combinations. Here we describe the update of research on the biology of MDR in the hematological malignancies and also discuss how to overcome MDR and adapt the updated treatment methods in the clinical medical field.
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PMID:Multidrug resistance in hematological malignancy. 1367 81

An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50% of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2% SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4% SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival.
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PMID:[Prognostic value of the expression of MDR-1 in acute myeloid leukemia]. 1451 39

Expression of two MDR genes, BCRP and MDR1, was evaluated by real-time PCR technique in 51 AML patients. Fifty-six percent expressed the BCRP gene, with the 48.2% showing intermediate levels. Eighty-eight percent expressed the MDR1, with 23.8% of cases at high expression. A significant correlation between BCRP and MDR1 values was found by regression analysis. Either levels of BCRP or MDR1 did not correlate with clinical characteristics of patients at diagnosis.
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PMID:Evaluation of BCRP and MDR-1 co-expression by quantitative molecular assessment in AML patients. 1554 85

Multidrug resistance is one of the mechanisms how to explain failure of chemotherapy in patients with different hematological malignancies. In this study we aimed to evaluate and compare the drug resistance in B-cell acute lymphoid leukemia (B-ALL) and multiple myeloma (MM) in association with their immunophenotypes and genotypes. Eleven patients with B-ALL and 14 patients with MM were classified according to prognostic factors. Standard MoAb panel for ALL and triple labeled antibodies (CD38/CD56/CD19) and detection of intracellular light chains for MM were used. Flow cytometric calcein assay was performed for measure of P- glycoprotein (MDR-1) and multidrug resistance associated protein (MRP-1) activity. Markers CD19, CD20 and HLA-DR proved to be useful in identifying cells of B-lymphoid lineage. CD34 progenitor cell antigen was present in high proportion of ALL blasts. Both the abnormal plasmacell populations and their monoclonality in MM were confirmed by immunophenotyping, too. The mean MDR activity factor (MAF) values were not different in patients with MM and B- ALL. However, the mean MRP-1 values in MM were significantly lower than MAF-MDR-1 (1.85+/-3.8 versus 5.92+/-7.45, p=0.05), but we have found lower values in refractory conditions as expected from previous studies of acute myeloid leukemia. The immunophenotyping was helpful in detection of abnormal populations showing no correlation with the MDR. However, in this study we could not confirm high MDR activity despite of the failure of chemotherapy. The calcein assay seems to be useful for quantitative and sensitive measurement of the MDR proteins. The low activity of MDR- 1 and MRP-1 in MM need further clarification, indicating the involvement of different transport in the resistance mechanism.
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PMID:Application of flow cytometry immunophenotyping and multidrug resistance assay in B-cell acute lymphoid leukemia and multiple myeloma. 1573 24

Seventy to 80% of patients with acute myeloid leukemia (AML) achieve complete remission (CR) by chemotherapy, but more than 50% of them then relapse. Phase III clinical trials in the treatment of patients with previously untreated AML and acute promyelocytic leukemia (APL) are ongoing in Japan (JALSG AML 201, APL 204). And continuous efforts are being made to improve the efficacy of chemotherapy. We discussed six topics in the treatment of AML. (1) To determine whether adding the MDR-1 modulator to chemotherapy provided clinical benefits to patients with AML and high-risk myelodysplastic syndrome (MDS), a phase III randomized study was performed using PSC 833. CR rates and overall survival (OS) were not improved by using PSC 833 compared to chemotherapy alone. (2) A large randomized study selectively focused on the G-CSF priming was performed. Among patients in this study attaining CR, the probability of relapse was reduced when they had been assigned to treatment with G-CSF along with induction chemotherapy. The benefit of chemotherapy-sensitization by G-CSF was particularly evident among the intermediate-risk. (3) Fludarabine in addition to Ara-C increases the accumulation of Ara-CTP, which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase III trial, patients with high-risk MDS or patients with AML were randomized to receive 2 induction courses consisting of Ara-C and G-CSF during and after chemotherapy with or without fludarabine (FLAG versus AG). Although Ara-CTP accumulation in leukemic cells after FLAG was enhanced, the clinical outcome in terms of CR rate, OS, event-free survival, and disease-free survival was not significantly improved by combining fludarabine with Ara-C. (4) Calicheamicin-conjugated humanized anti-CD 33 mouse monoclonal antibody, mylotarg, has recently been introduced. In combined phase II studies of 277 patients with CD 33-positive AML in their first relapse, the overall response rate was 26%. (5) Arsenic trioxide (ATO) has been established as a highly effective therapy for patients with APL, even for those with disease refractory to ATRA. ATO was recently approved in Japan. (6) There has been great interest in developing FLT 3 inhibitors because of the high frequency and poor prognosis of AML patients with mutant FLT 3. Some compounds are currently under development.
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PMID:[Current and new therapeutic strategies in acute myeloid leukemia]. 1579 11

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.
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PMID:Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000. 1613 67

The potential mechanism of the chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from acute myeloid leukemia. In a multicenter clinical trial, 38 patients with poor risk forms of AML were treated with tetrandrine (TET), a potent inhibitor of the MDR-1 efflux pump, combined with daunorubicin (DNR), etoposide and cytarabine (TET-DEC). Overall, post-chemotherapy marrow hypoplasia was achieved in 36 patients. Sixteen patients (42%) achieved complete remission or restored chronic phase, 9 achieved partial remission (PR) and 13 failed therapy. Toxicities included infection, myelosuppression, stomatitis, mucositis, cerebellar toxicity and reversible cardiotoxicity. There was no significant difference in response for P-gp-positive and -negative patients. P-gp function was assessed in 26 patients by flow cytometric analysis, TET-contained plasma-augmented DNR accumulation relative to pretreatment plasma in K562/A02 cells by a median value of 88+/-101% (range, 11-501%). However, there was no difference in DNR uptake between responding and non-responding patients. Our data showed that TET-DEC was relatively well tolerated in these patients with poor risk AML, and had encouraging antileukemic effects.
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PMID:Combination of tetrandrine as a potential-reversing agent with daunorubicin, etoposide and cytarabine for the treatment of refractory and relapsed acute myelogenous leukemia. 1621 52


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