scholarly journals Contribution of Multidrug Resistance Protein MRP5 in Control of Cyclic Guanosine 5′-Monophosphate Intracellular Signaling in Anterior Pituitary Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3435-3445 ◽  
Author(s):  
Silvana A. Andric ◽  
Tatjana S. Kostic ◽  
Stanko S. Stojilkovic
Keyword(s):  
Multidrug Resistance ◽  
Cyclic Nucleotide ◽  
Intracellular Signaling ◽  
De Novo ◽  
Critical Role ◽  
Gh3 Cells ◽  
Pituitary Cells ◽  
Multidrug Resistance Proteins ◽  
Cgmp Production ◽  
Camp And Cgmp

The energy-dependent cyclic nucleotide cellular efflux is operative in numerous eukaryotic cells and could be mediated by multidrug resistance proteins MRP4, MRP5, and MRP8. In pituitary cells, however, the operation of export pumps and their contribution to the control of intracellular cyclic nucleotide levels were not studied previously. Here we show that cellular efflux of cyclic nucleotides was detectable in normal and immortalized GH3 pituitary cells under resting conditions and was enlarged after concurrent stimulation of cAMP and cGMP production with GHRH, corticotropin-releasing factor, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and forskolin. In resting and stimulated cells, the efflux pumps transported the majority of de novo-produced cGMP, limiting its intracellular accumulation in a concentration range of 1–2 μm. In contrast, only a small fraction of cAMP was released and there was a time- and concentration-dependent accumulation of this messenger in the cytosol, ranging from 1–100 μm. Stimulation and inhibition of cGMP production alone did not affect cAMP efflux, suggesting the operation of two different transport pathways in pituitary cells. The rates of cAMP and cGMP effluxes were comparable, and both pathways were blocked by probenecid and progesterone. Pituitary cells expressed mRNA transcripts for MRP4, MRP5, and MRP8, whereas GH3 cells expressed only transcripts for MRP5. Down-regulation of MRP5 expression in GH3 cells decreased cGMP release without affecting cAMP efflux. These results indicate that cyclic nucleotide cellular efflux plays a critical role in elimination of intracellular cGMP but not cAMP in pituitary cells and that such selectivity is achieved by expression of MRP5.

scholarly journals Spontaneous and Receptor-Controlled Soluble Guanylyl Cyclase Activity in Anterior Pituitary Cells

2001 ◽  
Vol 15 (6) ◽  
pp. 1010-1022 ◽  
Author(s):  
Tatjana S. Kostic ◽  
Silvana A. Andric ◽  
Stanko S. Stojilkovic
Keyword(s):  
Adenylyl Cyclase ◽  
Guanylyl Cyclase ◽  
Anterior Pituitary ◽  
Soluble Guanylyl Cyclase ◽  
Gh3 Cells ◽  
Pituitary Cells ◽  
Cgmp Production ◽  
Pituitary Tissue ◽  
Anterior Pituitary Cells ◽  
Inducible Nos

Abstract Nitric oxide (NO)-dependent soluble guanylyl cyclase (sGC) is operative in mammalian cells, but its presence and the role in cGMP production in pituitary cells have been incompletely characterized. Here we show that sGC is expressed in pituitary tissue and dispersed cells, enriched lactotrophs and somatotrophs, and GH3 immortalized cells, and that this enzyme is exclusively responsible for cGMP production in unstimulated cells. Basal sGC activity was partially dependent on voltage-gated calcium influx, and both calcium-sensitive NO synthases (NOS), neuronal and endothelial, were expressed in pituitary tissue and mixed cells, enriched lactotrophs and somatotrophs, and GH3 cells. Calcium-independent inducible NOS was transiently expressed in cultured lactotrophs and somatotrophs after the dispersion of cells, but not in GH3 cells and pituitary tissue. This enzyme participated in the control of basal sGC activity in cultured pituitary cells. The overexpression of inducible NOS by lipopolysaccharide + interferon-γ further increased NO and cGMP levels, and the majority of de novo produced cGMP was rapidly released. Addition of an NO donor to perifused pituitary cells also led to a rapid cGMP release. Calcium-mobilizing agonists TRH and GnRH slightly increased basal cGMP production, but only when added in high concentrations. In contrast, adenylyl cyclase agonists GHRH and CRF induced a robust increase in cGMP production, with EC50s in the physiological concentration range. As in cells overexpressing inducible NOS, the stimulatory action of GHRH and CRF was preserved in cells bathed in calcium-deficient medium, but was not associated with a measurable increase in NO production. These results indicate that sGC is present in secretory anterior pituitary cells and is regulated in an NO-dependent manner through constitutively expressed neuronal and endothelial NOS and transiently expressed inducible NOS, as well as independently of NO by adenylyl cyclase coupled-receptors.

scholarly journals Dependence of Electrical Activity and Calcium Influx-Controlled Prolactin Release on Adenylyl Cyclase Signaling Pathway in Pituitary Lactotrophs

2006 ◽  
Vol 20 (9) ◽  
pp. 2231-2246 ◽  
Author(s):  
Arturo E. Gonzalez-Iglesias ◽  
Yonghua Jiang ◽  
Melanija Tomić ◽  
Karla Kretschmannova ◽  
Silvana A. Andric ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adenylyl Cyclase ◽  
Guanylyl Cyclase ◽  
Cyclic Nucleotide ◽  
Action Potentials ◽  
Soluble Guanylyl Cyclase ◽  
Cgmp Production ◽  
Camp And Cgmp ◽  
Kinase A

Abstract Pituitary lactotrophs in vitro fire extracellular Ca2+-dependent action potentials spontaneously through still unidentified pacemaking channels, and the associated voltage-gated Ca2+ influx (VGCI) is sufficient to maintain basal prolactin (PRL) secretion high and steady. Numerous plasma membrane channels have been characterized in these cells, but the mechanism underlying their pacemaking activity is still not known. Here we studied the relevance of cyclic nucleotide signaling pathways in control of pacemaking, VGCI, and PRL release. In mixed anterior pituitary cells, both VGCI-inhibitable and -insensitive adenylyl cyclase (AC) subtypes contributed to the basal cAMP production, and soluble guanylyl cyclase was exclusively responsible for basal cGMP production. Inhibition of basal AC activity, but not soluble guanylyl cyclase activity, reduced PRL release. In contrast, forskolin stimulated cAMP and cGMP production as well as pacemaking, VGCI, and PRL secretion. Elevation in cAMP and cGMP levels by inhibition of phosphodiesterase activity was also accompanied with increased PRL release. The AC inhibitors attenuated forskolin-stimulated cyclic nucleotide production, VGCI, and PRL release. The cell-permeable 8-bromo-cAMP stimulated firing of action potentials and PRL release and rescued hormone secretion in cells with inhibited ACs in an extracellular Ca2+-dependent manner, whereas 8-bromo-cGMP and 8-(4-chlorophenyltio)-2′-O-methyl-cAMP were ineffective. Protein kinase A inhibitors did not stop spontaneous and forskolin-stimulated pacemaking, VGCI, and PRL release. These results indicate that cAMP facilitates pacemaking, VGCI, and PRL release in lactotrophs predominantly in a protein kinase A- and Epac cAMP receptor-independent manner.

scholarly journals Role of Calcium-Calmodulin-Dependent Protein Kinase Cascade in Thyrotropin (TSH)-Releasing Hormone Induction of TSH and Prolactin Gene Expression

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4846-4852 ◽  
Author(s):  
Koji Murao ◽  
Hitomi Imachi ◽  
Wen M. Cao ◽  
Xiao Yu ◽  
Hiroshi Tokumitsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intracellular Signaling ◽  
Promoter Activity ◽  
Gh3 Cells ◽  
Dominant Negative Mutant ◽  
Pituitary Cells ◽  
Cam Kinase ◽  
Kinase Cascade ◽  
Dependent Protein

Abstract TRH binds to a membrane receptor that activates several intracellular signaling pathways and increases transcription of the TSH and prolactin (PRL) genes. Although TRH induces TSH and PRL gene expression, the underlying mechanism is not clear. In this report we examined the role of the Ca2+/calmodulin-dependent protein (CaM) kinase cascade in mediating TRH-stimulated transcription of TSH and PRL. RT-PCR and Western blot analysis were used to show that CaM kinase kinase (CaM-KK) and CaM IV (CaM-KIV) were present in rat anterior pituitary and its cell line GH3. Next, the effects of constitutively active CaM-KIV (CaM-KIVc) or its dominant negative mutant (CaM-KIVdn) on TSH and PRL promoter activity were tested in GH3 cells. The results showed that either CaM-KIVc alone or an upstream kinase, CaM-KK, induced the activity of both TSH and PRL promoters. Exposure of GH3 cells to 100 μm TRH induced CaM-KIV activity within 5 min and, as expected, also increased both TSH and PRL promoter activity. In contrast, cells carrying the CaM-KIVdn isoform had suppressed TRH induction of both TSH and PRL promoter activity. These results indicate that the CaM-KK-CaM-KIV cascade probably plays an important role in TRH induction of TSH and PRL transcriptional activity in pituitary cells.

Clinical Relevance of Multidrug Resistance Proteins Expression in Patients with De Novo Acute Myeloid Leukaemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4363-4363
Author(s):  
Maria Podolak-Dawidziak ◽  
Danuta Dus ◽  
Marek Kielbinski ◽  
Maria Paprocka ◽  
Olga Haus ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Acute Myeloid Leukaemia ◽  
Functional Activity ◽  
De Novo ◽  
Chemotherapy Cycle ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Cytogenetic Profile ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background. Early occurrence of the multidrug resistance (MDR) in de novo acute myeloid leukaemia (AML) may contribute to the treatment failure.The aim of this study was to investigate prospectively the clinical significance of the MDR proteins overexpression and their functional augmenting, in the context of other AML prognostic factors, such as age, immunophenotype and cytogenetic profile. We examined expression of MDR proteins: MDR1, MRP1, MDR3, BCRP, LRP and GSTπ and performed drug resistance functional assay in peripheral blood blasts of 25 patients with de novo AML at diagnosis and after the first chemotherapy cycle consisting of a 3 + 7 combination of DNR/Ara-C. MDR proteins presence and their functional activity (measured by fluorescent Rh123 dye efflux) were estimated by flow cytometry. Results: Thirteen out of the 25 AML patients (52%) attained a CR with induction treatment, one had PR and eleven did not achieve remission. Out of 10 patients without CR, 2 died in aplasia and 9 were classified as an early death due to disease progression. All patients who achieved remission were younger than 55 years. Among 11 patients without remission, 9 expressed CD34; 6 of them had intermediate and 5 unfovorable cytogenetic profiles. In 10 out of 25 patients (40%) overexpression od MDR1 was shown at diagnosis, and was irreversible in 9 of them, those with poor clinical outcome (6 did not achieve CR, 1 had PR and one who obtained CR relapsed), whereas one patient who reversed achieved CR. The functional MDR assay showed the increased Rh123 efflux, both at diagnosis and after the first chemotherapy cycle in 12 patients (48%) and it influenced patients’ outcome in similar manner as MDR1 expression. At diagnosis other MDR proteins were also elevated in some AML patients:GSTπin 19 (76%), LRP in 9 (36%), MRP in 4 (16%) and MDR3 in 2 (8%). Seven AML patients (20%), both at diagnosis and after the first chemotherapy cycle co-expressed MDR1 with other multidrug resistance proteins and had enhanced Rh123 efflux. This co-expression resultes in 6 of them in chemotherapy resistance; the remaining one who achieved remission was young and had favorable cytogenetic profile. The results obtained demonstrate that the advanced age, unfavorable cytogenetic profile, overexpression of MDR1 at diagnosis and co-expression of other MDR proteins together with their functional activity contribute to the treatment failure in de novo AML.

Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals

2014 ◽  
Vol 42 (2) ◽  
pp. 250-256 ◽  
Author(s):  
Donald H. Maurice ◽  
Lindsay S. Wilson ◽  
Sarah N. Rampersad ◽  
Fabien Hubert ◽  
Tammy Truong ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cyclic Nucleotide ◽  
Second Messengers ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Cellular Functions ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Cellular Processes ◽  
Camp And Cgmp ◽  
Nucleotide Phosphodiesterases

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that their ability to activate their multiple intracellular effectors is spatially and temporally selective. Studies have identified a critical role for compartmentation of the enzymes which hydrolyse and metabolically inactivate these second messengers, the PDEs (cyclic nucleotide phosphodiesterases), in this specificity. In the present article, we describe several examples from our work in which compartmentation of selected cAMP- or cGMP-hydrolysing PDEs co-ordinate selective activation of cyclic nucleotide effectors, and, as a result, selectively affect cellular functions. It is our belief that therapeutic strategies aimed at targeting PDEs within these compartments will allow greater selectivity than those directed at inhibiting these enzymes throughout the cells.

The Clinical Significance of the Multidrug Resistance Proteins Expression in Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4411-4411
Author(s):  
Maria Podolak-Dawidziak ◽  
Danuta Dus ◽  
Marek Kielbinski ◽  
Maria Paprocka ◽  
Malgorzata Kuliszkowicz-Janus ◽  
...  
Keyword(s):  
Septic Shock ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemia Cell ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Acute Myeloid

Abstract Multidrug resistance (MDR), connected with the overexpression of several proteins e.g. MDR1, MDR3, MRP1, LRP and BCPR, has been implicated in refractoriness to chemotherapy in acute myeloid leukemia (AML). The aim of this study was to evaluate their clinical significance and individual contributions to the drug resistant phenotype in AML We studied 22 untreated patients with de novo AML, 12 F and 10 M (aged from 20 to 74 years, mean 48.2 yrs) between Jan. 2002 and June 2004. Acc. to FAB classification 2 cases were M0, 2 M1, 10 M2, 6 M4, 2 M5. We performed rhodamine 123 (Rho123) accumulation and retention test and, simultaneously, evaluated MDR1, MDR3, MRP1, LRP and BCPR proteins, in flow cytometry analysis using specific monoclonal antibodies, with leukemic blasts gated with leukemia cell-specific antibodies. In all patients the examination was performed twice: at diagnosis time and 2 days after the first course of chemotherapy (daunorubicine and cytosine arabinoside). The sample was classified as a positive when the mean geometric canal of fluorescence intensity (FI) was 1.5-fold higher than that of the negative (isotypic antibody) control. 12 out of 22 pts are alive, 7 had CR and 5 had NR. Out of 7 CR pts 4 had all tests negative, both at diagnosis and after chemotherapy, in 1 case the positive tests at diagnosis were reversed after chemotherapy, and in 2 the Rho123 test was positive at diagnosis and after chemotherapy. Out of 5 who had NR, 4 were positive in both, the Rho 123 test and MDR1 prior to chemotherapy and thereafter, and all 5 NR pts expressed LRP after chemotherapy. Ten out of 22 AML pts died, in four due to disease progression and six in the septic shock. Out of 4 who died in relapse 3 had positive the Rho123 test and elevated MDR1, both at diagnosis and after chemotherapy, and the remaining 1 became positive after chemotherapy. In 6 who died in the septic shock the Rho 123 test was negative and the multidrug resistance proteins not expressed. Overexpression of MDR1 was detected in 7/22 pts at diagnosis, and was reversed after chemotherapy in 1 case (CR) and all 6 positive remained were refractory to chemotherapy (2 died, and the other 4 had NR). MDR1 appeared after chemotherapy in 3 pts and all of them died. In 9 out of 15 who did not respond to chemotherapy MDR1 was elevated after chemotherapy and 15 of them died. In six out of 22 AML elevated LRP was found at diagnosis and after chemotherapy; 5 were resistant to chemotherapy (3 died, 2 had NR) and only 1 achieved CR. And all five LRP -negative at diagnosis and further LRP- positive after chemotherapy, did not achieve remission (3 died and 2 had NR). 10 out of 15 resistant pts overexpressed LPR after chemotherapy and 6 of them died. In 4 AML pts MRP was elevated at diagnosis, and 3 of them in whom it reversed after chemotherapy are alive (1 CR and 2 had NR) and 1 in whom MRP remained positive died. Out of 2 AML pts in whom MRP became overexpressed after chemotherapy 1 died and 1 had NR. Elevated BCPR was found at diagnosis in 2 AML pts, after chemotherapy it was reversed in one (CR) and in one remained expressed (NR); in remaining 3 pts BCPR appeared after chemotherapy (2 of them died). We conclude, that the coexpression of several (at least two) multidrug resistance proteins is associated with an adverse prognosis and less CR.

Multidrug Resistance Proteins Overexpression Worsen the Favorable Clinical Impact of an Elevated Spontaneous Apoptosis in Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2315-2315
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Francesco Buccisano ◽  
Adriano Venditti ◽  
Luca Maurillo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
De Novo ◽  
Disease Free Survival ◽  
High Rate ◽  
Future Research ◽  
Prognostic Impact ◽  
Spontaneous Apoptosis ◽  
Multidrug Resistance Proteins ◽  
Monocytic Differentiation ◽  
Independent Events

Abstract Multidrug resistance (MDR) proteins (P-glycoprotein [PGP], lung resistance protein [LRP], multidrug related protein [MRP]) and apoptosis proteins (bcl-2, bcl-xl, bax) expression represent key mechanisms explaining the high rate of treatment failure in AML, as demonstrated also by gene expression profiling studies (Wilson CS et al, 2006). Therefore, from 1995 to 2006, a large series of 386 AML de novo pts, median age 58 years, treated with intensive chemotherapy regimens, was tested. The principal aims of our study were: to demonstrate that bax/bcl-2 ratio and MDR are critical and independent events; and to clarify whether MDR is able to modify the favorable outcome of pts with high spontaneous apoptosis. PGP, LRP, MRP, bcl-2 and bax proteins were determined by multicolor flow cytometry. Concurrent positivity for PGP, LRP and MRP defined the MDR positive subset (n=112). There were significant correlations between immature FAB classes (M0–M1) and lower bax/bcl-2 ratio (83/128; p<0.00001) or monocytic differentiation (M4-M5) and higher PGP expression (133/163; p<0.00001). A significant correlation was found between a higher PGP and a higher bax/bcl-2 ratio (153/224; p=0.02). MRP was more represented in pts with lower apoptosis (103/162; p=0.00005). A significant lower complete remission (CR) rate was found in pts with lower bax/bcl-2 ratio (41% vs 70%, p<0.00001) or higher MDR (35 % vs 74%, p<0.00001). Overall survival (OS) and disease free survival (DFS) were significantly shorter either in pts with lower bax/bcl-2 ratio (0% vs 20% at 3.5 years, p<0.00001; 0% vs 17% at 2.7 years; p=0.0001) or higher MDR (0% vs 27% at 2.5 years, p<0.00001; 5% vs 36% at 1.3 years; p=0.0001). Bax/bcl-2 ratio and MDR showed an additive prognostic impact, since higher bax/bcl-2 ratio plus lower MDR identified pts at better prognosis with regard to CR (89% vs 27%; p<0.00001), OS (41% vs 0% at 2.5 years; p<0.00001) and DFS (42% vs 0% at 1.2 years; p=0.0009). Noteworthy, also PGP, LRP and MRP showed an additive prognostic impact with regard to OS, since PGP+LRP+MRP+ pts (n=112) identified an AML subset (MDR) at worse outcome as compared to PGP+ or LRP+ or MRP+ alone (0% vs 7% or vs 6% or vs 3% at 2.5 years, respectively). In order to establish whether MDR overexpression is able to worsen the favorable clinical outcome of AML pts with elevated apoptosis levels, we analyzed the subgroup with higher bax/bcl-2 ratio (n=224). A lower CR rate was found in patients with higher MDR expression (47% vs 89%, p=0.0005). Equally, higher MDR expression was associated both with a shorter OS and DFS (5% vs 41% at 1.5 years, p<0.00001; 10% vs 42% at 1.3 years, p=0.003). The superior and independent prognostic value of bax/bcl-2 ratio over MDR proteins was confirmed in multivariate analysis with regard to CR (bax/bcl-2: p=0.0001; PGP: p=0.004), OS (bax/bcl-2: p=0.0001; LRP: p=0.02) and DFS (bax/bcl-2: p=0.0004; PGP: p=0.03; LRP: p=0.03). Therefore, low apoptosis and higher MDR in elevated apoptosis identify the two main different biologic AML subsets at worse prognosis. In fact, it has to be taken in account that the favorable prognostic impact of a higher bax/bcl-2 ratio may be greatly reduced by MDR positivity. Actually, we conclude that we have to focus future research and therapeutic strategies targeting in the first place apoptosis and then MDR proteins in AML.

Prognostic Significance of Multidrug Resistance Proteins Expression in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4360-4360
Author(s):  
Oleg D. Zakharov ◽  
Ekaterina U. Rybalkina ◽  
Alla A. Stavrovskaya ◽  
Maya Volkova
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Blast Cells ◽  
Acute Myeloid

Abstract Background: Conventional induction chemotherapy induces complete remission (CR) in 65–75% of adults with de novo acute myeloid leukemia (AML), and 15–20% of the patients have refractory disease. We investigated the prognostic significance of multidrug resistance proteins (P-glycoprotein (Pgp), BCRP, MRP1 and LRP) expression on AML blast cells before treatment. Methods: We included in analysis 30 patients (pts) with de novo AML. Expression of multidrug resistance proteins (MDR) was detected by indirect immunofluorescence technique and flow cytometry on bone marrow blast cells before chemotherapy. Expression of MDR proteins was considered as positive if at least 25% of the blast cells were stained by anti-MDR protein antibody. All pts received standard induction therapy (cytarabine, etoposide and idarubicin or daunorubicine). Results: Blast cells was defined as Pgp-positive in 64.3% of cases, BCRP+ in 42.9%, MRP1+ in 46.4%, and LRP+ in 64.3% of cases. After induction therapy 20 (66,7%) pts achieved CR and 10 pts (33.3%) were resistant. MDR proteins expression was observed more frequently in resistant group, then in a sensitive one (70% vs 61% for Pgp, 70% vs 33% for MRP1, 100% vs 44% for LRP, 80% vs 22% for BCRP, respectively), difference for LRP and BCRP was statistically significant (p=0.004). Blast cells of all resistant pts expressed 2–4 MDR proteins (all studied proteins − 40%, 3 of them − 40% and 2 proteins − 20%). In a group of pts archived CR the blast cells expressed 3 proteins only in 2 cases (10%), and the expression of all 4 proteins we observed only in 1 patient (5%) with very short CR duration (3 months). Other pts from this group express only one studied protein. According to chromosome analysis 18.2% of pts had favorable, 50% - intermediate and 31.8% unfavorable cytogenetic. Blast cells of all pts in cytogenetically unfavorable group expressed more then 1 protein, 3 or 4 MDR proteins expressed in 71,4% of cases. In favorable and intermediate cytogenetic groups blast cells expressed 1or 2 MDR proteins in 73,2% of cases, 3 or 4 proteins in 20%. Conclusions: The expression of MDR proteins in AML has a prognostic value with respect to CR achievement in pts receiving standard antracycline-Ara-C regimens. The detection of any single protein didn’t have prognostic significance, only co-expression of 2 and more proteins predict unfavorable treatment outcome. We observed a correlation between the cytogenetic and the MDR phenotype.

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