Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of the P-glycoprotein (Pgp), transmembrane drug efflux pump, has been shown to cause multidrug resistance of tumour cells (MDR). To investigate the clinical significance of Pgp expression for chronic myeloid leukaemia (CML) diagnosis and monitoring we have studied 38 CML patients in various phases of the disease (chronic phase, CP; accelerated phase, AP; blast crisis, BC). Anti-Pgp monoclonal antibody UIC2 and FACScan analysis were used. Pgp functional activity was investigated by evaluation of verapamil influence upon rhodamine 123 efflux from the cells. Correlations between Pgp and CD34 expression were investigated. In CP, Pgp-expressing cells were found in 2/14 patients; in one of them Pgp proved to be non-functional. There were few Pgp-expressing cells in AP cases. The group of BC patients consisted of cases resistant to chemotherapy. This gave us the opportunity to consider whether drug resistance of BC CML patients is preferentially connected with Pgp-mediated MDR. 11/22 BC patients had 20% or more of Pgp-expressing blasts in the peripheral blood. In all four Pgp+ BC cases studied for Pgp activity this protein was functional. Only 4/22 BC patients demonstrated large (40% or more) fractions of Pgp+ blasts. Moreover, sequential studies of 11 BC CML patients during treatment revealed an increase in the number of Pgp-expressing cells in only two cases. This suggests that Pgp+ cells did not often accumulate in BC CML patients due to chemotherapy and are the cause of drug resistance in only a few cases. A positive correlation between Pgp and CD34 expression was found (r = 0.69; P = 0.0004). 3/22 BC CML patients had large fractions of both Pgp+ and CD34+ blasts in their peripheral blood. The BC CML patients with this immunophenotype of blast cells may represent a subtype of BC CML resistant to treatment due to Pgp overexpression.
 ...
PMID:Studies of P-glycoprotein in chronic myelogenous leukaemia patients: expression, activity and correlations with CD34 antigen. 856 16

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.
 ...
PMID:Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. 863 Apr 12

The development of drug resistance was studied in a series of haemopoietic cells to determine its relationship to cell lineage. Treatment of the U937 monocytic cell line with epirubicin (15 ng/ml) or vinblastine (8 ng/ml) induced drug-resistant sublines with cross-resistance to epirubicin (8- and 16-fold respectively), vinblastine (5- and 20-fold), paclitaxel (15- and 42-fold) and etoposide (19- and 13-fold). However, sublines were also 3-5-fold resistant to the alkylating agent chlorambucil, cis-platinum and methotrexate, demonstrating an extended multidrug resistance (MDR) phenotype. These cells over-expressed P-glycoprotein, but decreased drug accumulation was not restored in the presence of verapamil, suggesting that the P-glycoprotein was not functional. Similar drug treatment of the HL60 promyelocytic cell line also produced sublines exhibiting an extended MDR phenotype. The KG1a and the HEL cell lines expressed functional P-glycoprotein and were resistant to the drug concentrations used for treatment. Multidrug resistance as mediated by P-glycoprotein cannot explain the resistance of CML patients to chemotherapy, especially in blast crisis. The induction of an extended MDR phenotype specifically in myeloid cells in response to drug treatment may explain the resistance observed in the treatment of CMI.
 ...
PMID:Extended multidrug resistance in haemopoietic cells. 898 31

Drug resistance often results in failure of anticancer chemotherapy in leukemias. Several mechanisms of drug resistance are known with multidrug resistance (MDR) being the best characterized one. MDR can be due to enhanced expression of certain genes (MDR1, MRP or LRP), alterations in glutathione-S-transferase activity or GSH levels and to reduction of the amount or the activity of topoisomerase II. Here we review the current status of the clinical significance of the various mechanisms of MDR in leukemias and also discuss possibilities for the reversal of MDR. MDR1 gene expression has been seen in many leukemias, notably in acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia. Both MDR1 RNA and P-glycoprotein expression of the leukemic cells have been shown to correlate with poor clinical outcome in AML. However, preliminary results indicate that the MRP gene as well as the LRP gene can be expressed in AML. Thus, drug resistance in leukemias appears to be multifactorial. P-glycoprotein-mediated MDR can be reversed by several drugs. These resistance modifiers are currently evaluated with regard to their clinical efficacy. Despite some encouraging results, reversal of drug resistance and subsequent improvement in clinical outcome remains to be shown.
 ...
PMID:Multidrug resistance in leukemias and its reversal. 903 Oct 75

The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp. expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m2/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m2/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment.
 ...
PMID:Idarubicin monotherapy in multiply pretreated leukemia patients: response in relation to P-glycoprotein expression. 906 74

P-glycoprotein (Pgp) mediated multidrug resistance is often the cause of therapy failure in some tumors. Pgp expression was shown to have prognostic value in several hematological malignancies, especially in acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). In chronic myeloid leukemia (CML) Pgp is expressed by peripheral blood (PB) cells more often in the terminal disease stages (20-50% of patients have Pgp+ phenotype). Sequential studies show that Pgp+ cells often disappear from the PB during the course of therapy. Nevertheless Pgp expression has some prognostic value in blast crisis (BC) predicting shorter BC, while CD13 has the same predictive value in BC. 10% of patients formed a distinct group with large numbers of Pgp+CD34+ blasts in the PB and also had shorter BC. Cases with inactive Pgp were found in chronic and accelerated phases of CML but not in BC.
 ...
PMID:Prognostic value of P-glycoprotein and leukocyte differentiation antigens in chronic myeloid leukemia. 961 76

Drug resistance is a common cause of treatment failure in oncology. In addition to the resistance caused by over-expression of p-glycoprotein and similar molecules other mechanisms are involved in the selection or induction of drug resistant tumor cells. In this study, we characterized a CML cell line made resistant to cyclophosphamide (KBM7-B5-1803) further for the expression of apoptosis promoting and inhibiting molecules. We found that KBM7-B5-1803 has a 3 4-fold over-expression of the receptor CD95 (Fas/Apo-1) compared with the parent line. The regulation of CD95 by cytokines was comparable to other types of cells. Despite the inducibility and over-expression of CD95, CD95 failed to trigger apoptosis in both the parent and the drug resistant line. The drug resistant line has a particular pattern of the expression of bcl-2 family members: bcl-2 protein and message were expressed to a similar extent, however, compared with the parent line, the message for bclx short was decreased. P-glycoprotein was not expressed in either cell line. Taken together we show here in a leukemia cell line that the phenotype of cyclophosphamide resistance is associated with a particular pattern of apoptosis-related molecules.
 ...
PMID:Further characterization of cyclophosphamide resistance: expression of CD95 and of bcl-2 in a CML cell line. 978 11

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expression by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P =.01) and Pgp function (P =.03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts (P <.05). A good correlation between increased Pgp expression and function was observed in Pgp-negative (r =.90, P =.0001) and Pgp-positive blasts (r =.77, P =.0002). This increase in Pgp expression and function was inhibited by the addition of 1 micromol/L PSC 833 to blast cells at the time of their exposure to these cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo at 4 and 16 hours after the administration of standard chemotherapy with DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harvested at the time of presentation. These data suggest that upregulation of the MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.
 ...
PMID:Altered multidrug resistance phenotype caused by anthracycline analogues and cytosine arabinoside in myeloid leukemia. 1036 Nov 5

The non-ionic detergent Tween 80, which is used as a solvent for lipophilic drugs such as VP-16 and Taxotere, was found to reverse VP-16 resistance of the P-glycoprotein-associated multidrug resistance phenotype via increasing VP-16 influx. In adriamycin-resistant human chronic myelogenous leukemia K562 cells (K562/ADM), which overexpress mdr1 mRNA, the accumulation of VP-16 was only about 10% that in wild-type K562 cells. Tween 80 enhanced VP-16 accumulation in K562/ADM cells but did not influence VP-16 accumulation in parental K562 cells. VP-16 efflux was rapid and similar in both sensitive and resistant cell lines and was not blocked by Tween 80 or verapamil. Under glucose-free conditions, VP-16 accumulation in K562/ADM cells was only half of that in K562 cells. Tween 80 increased VP-16 accumulation in K562/ADM cells in glucose-free medium. In growth inhibition assay, Tween 80 reversed K562/ADM sensitivity to VP-16 without cell damage. Taken together, Tween 80 reverses VP-16 sensitivity in multidrug-resistant K562 cells by increasing influx, which is considered to be the primary mechanism of VP-16 resistance in K562/ADM cells.
 ...
PMID:Non-ionic detergent Tween 80 modulates VP-16 resistance in classical multidrug resistant K562 cells via enhancement of VP-16 influx. 1073 19

Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 micromol/L) than in the sensitive (0.2-0.25 micromol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC(50) for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL.
 ...
PMID:Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. 1091 Sep 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>