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)

Determination of the MDR-phenotype in patients suffering from AML is an important hallmark of treatment outcome but is often complicated by technical problems in P-gp assessment. A PCR-MIMIC strategy was employed to construct PCR-fragments for a competitive and quantitative mdr1 reverse transcription-PCR-assay. Using K562 cells, which had been selected for drug resistance to the epipodophyllotoxin VP16, a stepwise increase of mdr1 levels depending on the concentration of VP16 was shown with the MIMIC technique. Comparison of mdr1 levels in drug selected K562 cells with the corresponding levels for P-gp and functional data indicated a mRNA threshold that has to be exceeded for the full expression of the MDR-phenotype. Subsequently mdr1 levels of 34 samples of de novo acute myeloid leukemia were determined with the PCR-MIMIC strategy. Ten patient samples could be identified with elevated mdr1 levels which were substantially lower than the levels observed in the MDR-cell line K 562 0.7 microM VP16. Outcome analysis revealed that eight of the ten patients had an unfavourable prognosis and did not achieve CR after induction chemotherapy. Coexpression of mdr1 and CD 34 was not associated with CR in all examined cases. Moreover all these patients had unfavourable cytogenetic aberrations. These data indicate a sensitive technique with applicability in patient material.
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PMID:A new PCR MIMIC strategy to quantify low mdr1 mRNA levels in drug resistant cell lines and AML blast samples. 1040 Jan 87

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.
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PMID:Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. 1041 2

In order to bring MDR analysis into a clinical setting, reproducible assays with clear cut off points to define MDR positivity must be used. Sensitivity can also be increased by combining the results of more than one assay. We have used a combination of flow cytometric assays to define MDR positive and negative blasts in 47 AML patients entered into MRC trials. Our primary test is a standardised and reproducible assay for anthracycline accumulation in which we use carboxylate microspheres to bind the fluorescent drug daunorubicin (dnr). Cells and beads are incubated concurrently with dnr. Cellular dnr accumulation is quantified as a cell:bead fluorescence ratio. Confirmatory assays for MDR comprise the cyclosporin modulation assay for rhodamine 123 uptake and also measurement of lung resistance protein and multidrug resistance associated protein (with LRP-56 and MRPr1 respectively). 27/47 (57%) samples had both low and accumulation and at least one positive confirmatory test (a modulated functional assay and/or protein overexpression) and were categorised as "confirmed MDR". 15/47 patients (32%) were MDR negative in all 4 assays. 5/47 (11%) patients had unconfirmed low dnr accumulation. None of the patients in this cohort had high dnr accumulation alongside overexpressed LRP or MRP or functional P-glycoprotein. We believe that this approach to MDR analysis enhances the value of the highly reproducible functional assays. The use of a primary and confirmatory tests is also likely to improve specificity.
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PMID:Reproducible flow cytometric methodology for measuring multidrug resistance in leukaemic blasts. 1050 Jul 83

Although the prognosis for adults with acute myelogenous leukemia (AML) has improved over the past 10 years, overall results remain modest. Current research areas in the treatment of AML include dose-intensive therapy and stem-cell transplantation (SCT), immunotherapy, modulation of leukemia resistance (eg, multidrug resistance [MDR] Inhibitors), differentiation therapy (eg, retinolds), exploitation of different disease pathophysiology (eg, angiogenesis inhibitors, apoptosis-inducing agents), targeted therapy (eg, monoclonal antibodies, gene therapy), and the development of additional active chemotherapeutic agents with different mechanisms of action. Topotecan, a topoisomerase-I Inhibitor, may potentially enhance the activity of standard induction chemotherapy with cytosine arabinoside (cytarabine) and topoisomerase-II inhibitors. Topotecan is being investigated as salvage and front-line therapy for AML in combination with etoposide, cytarabine, or cyclophosphamide. The role that topotecan will eventually play In the treatment of AML is not yet clear, but encouraging results from triple combination induction therapy In patients with unfavorable prognoses warrant further investigation.
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PMID:New developments in the treatment of acute myeloid leukemia: focus on topotecan. 1062 25

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.
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PMID:A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617. 1086 30

Drug compartmentalization as well as drug efflux can contribute to drug resistance. We demonstrate the presence of P-gp in intracellular vesicles in certain AML cell lines and show localization of DNR to a similar subcellular compartment(s) that can be altered in the presence of P-gp inhibitors. Analysis of leukaemic cell lines and 50 AML patient samples showed that the level of P-gp mRNA or total P-gp protein correlated better with drug efflux than surface P-gp protein, suggesting that intracellular P-gp may contribute to MDR in AML. Therefore, the level of total P-gp protein or mRNA may be a better indicator of MDR than surface P-gp protein. In addition, we provide evidence for a novel mechanism of drug sequestration in K562 myeloid leukaemic cells.
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PMID:Intracellular P-gp contributes to functional drug efflux and resistance in acute myeloid leukaemia. 1130 Nov 7

Efflux of Hoechst 33342 from normal hematopoietic cells identifies a "side population" (SP(+)) of negatively staining cells that, in the mouse, are largely CD34(-) and are enriched for primitive progenitors. To further characterize human SP(+) cells, blood or bone marrow from 16 patients with acute myeloid leukemia (AML) was analyzed for their presence, immunophenotype, and cytogenetic and functional properties, and for the relation between SP phenotype and multidrug resistance-1 (MDR-1) expression. The mean percentages of SP(+) and MDR(+) cells was 8.1% (range, 0.5%-29.9%) and 12.8% (range, 0%-54.8%), respectively, with no correlation between the 2 values. The percentages of SP(+) cells that were CD34(+)CD38(-), CD34(+)CD38(+), or CD34(-) were 12% (range, 0.4%-50%), 25% (range, 0.5%-96%), and 63% (range, 4%-99%). Cytogenetically abnormal cells were always detected in the SP(-)CD34(+)CD38(-) and SP(+)CD34(-) fractions, and abnormal colonies (CFC), long-term culture-initiating cells (LTC-IC), and nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mouse leukemia-IC were detected in the former fraction. No progenitors were detected among SP(+)CD34(-) cells in any of these assays from 9 of 10 samples. In contrast, exclusively normal cells were detected in the SP(+)CD34(+)CD38(-) fraction from 9 of 15 samples, and CFC, LTC-IC, and multilineage engraftment in NOD/SCID mice from this subpopulation were also cytogenetically normal in 6 of 8, 6 of 7, and 2 of 2 cases studied, respectively. In contrast to murine studies, primitive progenitors are enriched among SP(+)CD34(+)CD38(-) cells from patients with AML. The molecular basis for Hoechst dye efflux is uncertain because it does not appear to be related to MDR-1 expression. (Blood. 2001;97:3882-3889)
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PMID:Hoechst 33342 efflux identifies a subpopulation of cytogenetically normal CD34(+)CD38(-) progenitor cells from patients with acute myeloid leukemia. 1138 30

In order to assess any correlation between MDR-1 expression and chromosomal aberrations, and to define their impact on clinical outcome in newly diagnosed AML pts, we investigated bone marrow and peripheral blood samples of 49 consecutive pts admitted to our hospital. Monosomy 7, trisomy 8 and 5q- were evaluated by means of interphase fluorescence in situ hybridization (FISH). Monosomy 7 was present in 6 pts, trisomy 8 in 5 pts, and 5q- in 6 pts. More than one aberration was seen in 7 pts. Chromosomal aberrations were mostly found in older pts (12/14 >60 years; p=0.03) and in pts with CD34 positive leukemic blasts (13/14 coexpressed CD34, p=0.0004). In 25 pts also standard G-banding analysis was performed leading to concordant results regarding chromosomes 7, 8 and 5. Flow cytometry identifyed MDR-1 positivity (MDR+) in 16 pts. MDR-1 expression appeared to be a characteristic feature in CD34+ AML (12/16 were CD34+ and MDR+ pts; p=0.013). No correlation, however, was found between chromosomal aberrations and MDR-1 expression. Pts with aberrations of either chromosomes 7, 8 or 5 detected by FISH (FISH+) were predominantly resistant to induction therapy (6/8 pts, p=0.004). A lower rate of complete remission (CR) was also seen in pts with MDR-1 expression (p=0.006). MDR+/FISH+ pts (n=3) were all refractory to remission induction, while all MDR-/FISH- pts (n=19) achieved CR (p=0.0006). MDR-1+ as well as pts with aberrations of chromosomes 7, and 5(q) showed a significantly decreased probability of overall survival. In conclusion, MDR-1 expression as well as abnormalities of chromosomes 7, and 5(q) predict poor clinical outcome in AML. The identification of these prognostic factors provides useful information for risk adapted treatment strategies.
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PMID:MDR-1 expression and deletions of chromosomes 7 and 5(Q) separately indicate adverse prognosis in AML. 1142 33

Allelic variants of the MDR-1 gene have been shown recently to influence protein expression and P-glycoprotein (P-gp) function in healthy volunteers. Therefore, 405 acute myeloid leukemia patients were investigated for somatic genotypes of the three most frequent single nucleotide polymorphisms (SNPs) in exons 12, 21, and 26. In all three loci, homozygous wild-type alleles were classified as genotype A, heterozygous as B, and homozygous mutant (alternative) allele as C. Patients with the C genotype in exons 12 and 26 showed a lower median age (both P < 0.05). Additionally, the C genotype in exons 12 and 26 was associated with cytogenetic poor risk aberrations (both P < 0.05). A possible regulatory impact of the SNPs on MDR1 mRNA expression was investigated by a Real time-PCR assay. MDR1 expression was strongly correlated with a decreased complete remission rate (P = 0.01) but failed to predict decreased overall survival (OS). There was a significant association of the A genotype in exons 21 (P = 0.05) and 26 (P < 0.05) with lower MDR1 expression, whereas the B variants showed highest MDR1 values at all three investigated gene loci. The A genotype in exon 26 was associated with lower OS (P < 0,01). In these patients, worse OS is likely attributable to an increased risk of relapse (P < 0.001). We were able to detect a linkage disequilibrium of the investigated SNPs, indicating combined polymorphisms that could affect the regulation of MDR1 expression. The A genotype of all SNPs demonstrated both lowest MDR1 values and significantly decreased OS (P < 0.05) with a high probability of relapses (P < 0.01). These observations indicate that allelic variants of the MDR1 gene may influence therapy outcome by additional mechanisms, different from P-gp expression on acute myeloid leukemia blasts, possibly involving pharmacokinetic effects of P-gp.
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PMID:MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. 1220 46

The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy.
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PMID:The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines. 1238 33


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