Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the self-renewal capacity (PE2) and in vitro sensitivity to cytosine-arabinoside (ara-C) and daunorubicine (DNR) of leukemic progenitors (CFU-AML) to determine the significance of these tests for predicting induction treatment outcome in 75 adult acute myeloid leukemia (AML) patients. In addition, in a part of this group of patients (n = 46) we determined the expression of P-glycoprotein (P-gp) immunocytochemically and correlated those results with the therapeutic response. We have evaluated 66 patients who showed the following responses: 28/66 complete remissions (CR), 16/66 resistant leukemias (RL) and 22/66 early deaths (ED). The PE2 value was significantly higher in patients with RL than in patients with CR (p < 0.00375). CFU-AML sensitivity to ara-C and DNR alone was not different between response groups, but the difference in CFU-AML sensitivity to the combination of drugs between patients with CR and RL was not significant, although a trend was noted (p < 0.06). P-gp expression was found in only 1/18 patients who achieved CR but in 9/11 patients with RL and 7/11 patients with ED, which is a highly significant difference (p < 0.0006). We concluded that both PE2 and P-gp expression in AML cells are valuable predictors of therapeutic response in adult AML and should be included in creating the best therapeutic approach to AML patients.
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PMID:In vitro drug sensitivity of leukemic progenitors and P-glycoprotein expression in adult acute myeloid leukemia: correlation with induction treatment outcome. 762 94

The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML). In the present study, multiple aspects of topo II-mediated drug action were examined in marrows from adult AML patients. Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA required to diminish leukemic colony formation by 90% (LD90) varied over a greater than 20-fold range between different pretreatment marrows. Measurement of nuclear DNR accumulation in the absence and presence of quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82 samples at diagnosis and 5 of 36 samples at first relapse, but the largest quinidine-induced increment in DNR accumulation (< 2-fold) was too small to explain the variations in drug sensitivity. Restriction enzyme-based assays and sequencing of partial topo II alpha and topo II beta cDNAs from the most highly resistant specimens failed to demonstrate topo II gene mutations that could account for resistance. Western blotting of marrow samples containing greater than 80% blasts revealed that the content of the two topo II isoenzymes varied over a greater than 20-fold range, but did not correlate with drug sensitivity in vitro or in vivo. In addition, levels of topo II alpha and topo II beta in 46 of 47 clinical samples were lower than in human AML cell lines. Immunoperoxidase staining showed that these low topo II levels were accompanied by marked cell-to-cell heterogeneity, with topo II alpha being abundant in some blasts and diminished or absent from others. There was a trend toward increasing percentages of topo II alpha-positive cells in pretreatment marrows that contained more S-phase cells. Consistent with this observation, treatment of patients with granulocyte-macrophage colony-stimulating factor for 3 days before chemotherapy resulted in increases in topo II alpha-positive cells concomitant with increases in the number of cells traversing the cell cycle. These observations have implications for the regulation of topo II in AML, for the use of topo II-directed chemotherapy, and for future attempts to relate drug sensitivity to topo II levels in clinical material.
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PMID:Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. 790 87

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

Two proteins that have been correlated with the occurrence of multidrug resistance in acute myeloid leukemia (AML) are P-glycoprotein (Pgp) and the major vault protein (Mvp/LRP). With the purpose of further quantifying the potential contributions of Pgp-mediated drug efflux and Mvp/LRP to drug resistance in AML we have investigated whether the transport function of Pgp and the expression of Mvp/LRP correlated with the accumulation of daunorubicin (DNR) and the in vitro resistance to DNR cytotoxicity (LC50 by MTT assay) in AML cells. In de novo adult AML, the steady-state DNR accumulation (in pmol/10(6) cells) correlated with Pgp activity or expression, whereas the LC50 for DNR did not correlate with Pgp activity (measured as the modulation of rhodamine 123 or DNR accumulation by the Pgp inhibitor PSC833) or Pgp expression (measured by flow cytometry with the MRK-16 antibody). The contribution of MRP1 expression to a reduced DNR accumulation seems minor compared to Pgp. In addition, the modulation of the DNR LC50 by PSC833 did not correlate with Pgp protein or activity. The steady-state DNR accumulation showed no correlation with the DNR LC50. The Mvp/LRP expression (immunocytochemical staining) did neither correlate with DNR accumulation nor with the DNR LC50. A significant negative correlation was seen between the Mvp/LRP immunocytochemical staining and Pgp activity, indicating that both markers define (partially) different populations. In conclusion, it is shown that Pgp function, but not Mvp/LRP or MRP1 expression correlate with a low steady-state DNR accumulation in de novo AML. The Pgp activity does, however, not predict the DNR sensitivity in AML measured as in vitro DNR LC50 with an MTT-based assay. The reason for that seems to be that a low DNR accumulation may not be the most important factor in determining the LC50. While the clinical usefulness of these drug resistance tests remains to be proven they do not seem to provide as yet a straightforward explanation for the major cause(s) of clinical chemotherapy failure.
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PMID:Do P-glycoprotein and major vault protein (MVP/LRP) expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia? 1048 3

To evaluate the clinical and biological significance of P-glycoprotein (P-gp) expression in adult acute nonlymphocytic leukemia (ANLL), P-gp was detected in 169 patients including 152 previously untreated cases, 7 refractory cases, and 10 cases at remission by using monoclonal antibody UIC2 and flow cytometry. P-gp was expressed in 29% of previously untreated cases, being less than in 71% of the refractory cases. P-gp expression was not found in patients at remission. Morphologically, P-gp expression was high in hybrid acute leukemia (67%) and acute monoblastic leukemia (47%) subtypes. Immunologically, P-gp expression was significantly associated with CD34, CD7, CD14 or CD42b/CD61. Cytogenetically, P-gp expression was highly associated with poor prognosis abnormalities (54%), which was significantly higher than 7% of P-gp expression in good prognosis abnormalities. 23% of P-gp positive previously untreated ANLL (not including M3) achieved complete remission; this was significantly lower than 76% in P-gp negative cases. These suggested that P-gp expression is an index of poor prognosis in adult ANLL and P-gp positive ANLL has unique clinical and biological features.
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PMID:[The clinical and biological significance of P-glycoprotein expression in acute nonlymphocytic leukemia]. 1037 70

Clinical and biological features were assessed in 204 consecutive de novo adult acute myeloid leukemia (AML) patients who received intensive chemotherapy regimens. Multiparameter flow cytometric assays both of the multidrug resistance (MDR-1)-associated P-glycoprotein (PGP) using the UIC2 monoclonal antibody (MoAb), and of terminal transferase (TdT) were performed. Cytogenetic findings were obtained from 196 patients with high resolution banding. At onset, UIC2 and TdT positivities were detected in 58.5% and 24% of cases, respectively. There were strict correlations either between UIC2 negativity and FAB M3 or between TdT and FAB M0-M1 (P = 0.001 and < 0.0001, respectively). On the other hand, age was significantly associated with cytogenetic risk classes (P < 0.0001). CD34 positivity was highly correlated with TdT expression (P < 0.0001). Moreover, CD7 and CD11b were significantly represented in UIC2+ subset (P < 0.0001). Rhodamine 123 (Rh 123) efflux was significantly higher in 75 UIC2 positive patients compared to 65 UIC2 negative ones (P < 0.001). As regards to cytogenetics, TdT positivity was strongly related either to t(9;22) or single/associated anomalies of chromosome 7; on the other hand, most or all cases with t(8;21) or t(15;17) were UIC2 or TdT negative, respectively. The rate of first complete remission (CR) differed both between UIC2+ and UIC2- cases and between TdT+ and TdT- ones (40% versus 72%, P < 0.001; and 36% versus 61%, P = 0.001, respectively). The survival rates (Kaplan-Meier method) were significantly shorter either in UIC2+ or in TdT+ patients (P = 0.005 and = 0.011, respectively). UIC2 and TdT negative cases showed longer remission duration (P = 0.03 and = 0.22, respectively). The additional effect of UIC2 and TdT on prognosis allowed us to identify two subsets of patients, the first [UIC2- TdT-] at better and the second [UIC2+ TdT+] at worse clinical outcome compared to single UIC2 and TdT cases, concerning CR (P < 0.001), survival (P < 0.0001) and CR duration (P = 0.007). The combinations [UIC2+ TdT-] and [UIC2- TdT+] showed an intermediate clinical course. A strong difference was found between poor risk and intermediate/favorable risk cytogenetic classes with regard to CR rate (P < 0.0001), overall survival and CR duration (P < 0.001). Nevertheless, within the poor risk class, UIC2 positivity was able to identify patients at worst prognosis with regard to CR (P = 0.005), survival (P = 0.02) and CR duration (P = 0.015). On the other hand, UIC2 and TdT negativity allowed us to distinguish patients with longer survival (P = 0.012 and = 0.04, respectively) and CR duration (P = 0.04 and = 0.025, respectively) within the intermediate/favorable risk class. The independent prognostic value of UIC2, TdT and cytogenetic risk classes was confirmed in multivariate analysis. These results suggest that PGP and TdT expressions, together with cytogenetic findings, may represent a basic predictor of chemotherapeutic failure in AML.
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PMID:P-glycoprotein and terminal transferase expression identify prognostic subsets within cytogenetic risk classes in acute myeloid leukemia. 1037 59

The multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance-related proteins (MRPs) are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Three-dimensional modeling of human MDR1/P-gp indicates that these glycoproteins function as efficient, ATP-dependent gate-keepers, which scan the plasma membrane and its inner leaflet to flip lipophilic substrates to the outer membrane leaflet. Delineation of the adverse prognostic power of MDR1 in adult acute myeloid leukemia (AML) raised hopes that pharmacologic blockade of P-gp would improve the outcome of conventional cytotoxic therapy, perhaps more so than in any other human malignancy. Phase 3 clinical trials investigating first- and second-generation P-gp antagonists have yielded conflicting results, emphasizing the importance of applying preclinical principals to realistically appraise expectations for clinical benefit. Structure-based design strategies and the delineation of transcriptional regulators of survival gene cassettes promise to yield novel, more-effective strategies to overcome drug resistance. Lessons learned from investigations of these and other mechanisms of cellular defense hold promise for a renaissance in the development of targeted therapeutics in acute leukemia.
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PMID:Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. 1565 19

Inherited differences in xenobiotic transport and metabolism may play an important role in the development of adult acute myeloid leukemia (AML) and response to the chemotherapy. An ATP-binding cassette (ABC) family transporter P-glycoprotein (P-gp or ABCB1), encoded by ABCB1 (MDR1) gene, is involved in the protection against xenobiotics and multi-drug resistance. The aim of this study was to investigate the potential involvement of the ABCB1 gene exon 26 3435C>T single nucleotide polymorphism (SNP) in the genetic susceptibility to AML and regulation of P-gp expression and activity in AML cells. A total of 180 adult AML patients and 180 sex-matched controls were genotyped using PCR-RFLP method. Moreover, in 40 AML patients ABCB1 gene expression was studied by real-time RT-PCR and P-gp expression and activity were assessed by flow cytometry assays. The prevalence of 3435C>T ABCB1 polymorphism was similar in patient and control cohorts (P = 0.16). Furthermore, the carriers of different ABCB1 genotypes did not differ significantly according to ABCB1 gene expression (P = 0.99), P-gp expression (P = 0.42) and P-gp activity (P = 0.83) in leukemic cells. The authors conclude that isolated 3435C>T ABCB1 SNP is not a major factor of the genetic susceptibility to adult AML, and that genotyping of this polymorphism does not allow predicting P-gp expression or activity in AML cells.
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PMID:No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells. 1703 91