Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.
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PMID:Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. 1464 19

Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.
Leukemia 2004 Mar
PMID:P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. 1472 52

A relatively well documented and seemingly firm overall picture of mechanisms involved in leukemia-cell drug resistance has evolved since the 1970s, where mechanisms involved in multidrug resistance towards anti-leukemia chemotherapeutic compounds were first described. At that time, based on available data, resistance associated with overexpression of the cell-surface transmembrane ATPase P-glycoprotein (P-170, P-gp, the product of the MDR1 gene) was described as "the" cause of multidrug resistance in cancer cells. However, during the 1980s and later on other mechanisms were described as candidate causes of multidrug resistance in human leukemia. Moreover, research of the past decade has provided us with an enormous increase in the amount of data and knowledge on the cell-biological and--to an even higher extent--the molecular-genetic processes governing cell survival and death in cancer cells. This, in turn, has improved the possibilities of designing and developing better drugs and drug combinations in leukemia. Along this line, based on rational drug design, imatinib, a 2-phenylaminopyrimidine derivative, has very recently been introduced and found to be an efficient inhibitor of the altered tyrosine kinase, which arises as a product of the BCR-ABL fusion transcript in Philadelphia chromosome positive (Ph+) cases of CML. This new compound appears to be the first of a (hopefully) large family of small organic molecules with a more specific inhibiting activity against the pathogenetic defects in leukemia as well as cancer. With this novel compound, as with all other known individual drugs and classes of chemotherapeutic drugs, drug resistance is seen. To what extent drug resistance towards this novel compound (and its successors) will follow patterns of drug resistance that are already known or entirely new mechanisms of drug resistance is yet to be seen.
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PMID:Changing picture of cellular drug resistance in human leukemia. 1509 58

The MDR1 gene is a key component of the cytotoxic defense network and its overexpression results in the multidrug resistance (MDR) phenotype. However, the molecular mechanisms that regulate the MDR1 gene and coordinate multiple MDR-related genes expression are poorly understood. In a previous study, we identified a new 12 bp cis-activating region in the 5'-flanking region of the human MDR1 gene, which we called inverted MED1. In the present study, we characterized the precise binding element, which we named invMED1, and revealed the presence of the LRP130 protein as the nuclear factor. Its binding intensity increases with the endogenous MDR1 geneexpression and with the MDR level of CEM leukemia cells. Interestingly, the LRP130 level did not vary with the chemoresistance level. We observed the involvement of LRP130 in the transcriptional activity of the MDR1 gene promoter, and moreover, in that of the MDR-related, invMED1-containing, MVP gene promoter. We used siRNAs and transcriptional decoys in two unrelated human cancer cell lines to show the role of the invMED1/LRP130 couple in both MDR1 and MVP endogenous genes activities. We showed that invMED1 was localized in the -105/-100 and -148/-143 regions of the MDR1 and MVP gene promoters, respectively. In addition, since the invMED1 sequence is primarily located in the -160/-100 bp region of mammalian MDR-related genes, our results present the invMED1/LRP130 couple as a potential central regulator of the transcription of these genes.
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PMID:New invMED1 element cis-activates human multidrug-related MDR1 and MVP genes, involving the LRP130 protein. 1527 88

Overexpression of human MDR1 P-glycoprotein [Pgp] is associated with cellular resistance to bulky amphipathic drugs, such as taxol, anthracyclines, vinca alkaloids, and epipodophyllotoxins by actively effluxing drugs from cells. We have found that human MDR1 transfected murine L1210/VMDRC.06 leukemia cells exhibit relatively large amounts of Pgp and high levels of resistance to 6-mercaptopurine [6-MP] and other purine and pyrimidine nucleobase and nucleoside analogs. L1210/VMDRC.06 cells accumulated 6-MP as the nucleotide in vitro at only about one-third of that formed by parental L1210 cells in normal medium; however, under conditions of ATP-depletion, the amount of 6-MP nucleotide formed was essentially the same in both cell lines. The findings support active efflux of 6-MP in L1210 cells, suggesting involvement of Pgp in 6-MP resistance even though it is generally believed that Pgp does not transport such agents. The resistance pattern observed in L1210/VMDRC.06 cells was not duplicated in P388/VMDRC.04 leukemia cells transfected with the same MDR1 cDNA, even though a similar amount of Pgp was present in both cell lines. Immunofluorescent staining of surface membrane Pgp showed that L1210/VMDRC.06 cells contained at least three-fold more surface Pgp than P388/VMDRC.04, implying that P388/VMDRC.04 cells are unable to actively efflux 6-MP and other antimetabolites as effectively as L1210/VMDRC.06, because of significantly lower membrane Pgp. The findings suggest that the exceedingly large concentration of overexpressed Pgp in the surface membrane of L1210/MDRC.06 cells is responsible for resistance to 6-MP and other purine and pyrimidine analogs, even though these agents usually are not considered to be substrates for Pgp.
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PMID:Resistance to purine and pyrimidine nucleoside and nucleobase analogs by the human MDR1 transfected murine leukemia cell line L1210/VMDRC.06. 1529 54

The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells. 1537 75

XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and in vivo, against several murine and human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of a variety of solid tumors (n = 90) and a CCRF-CEM leukemia cell line selected with XR5944. Differences in gene expression between the parental CCRF-CEM and the resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I and IIalpha and multidrug resistance (MDR1) protein was done on those tumors for which tissue was available (n = 32). The CCRF-CEM XR5944 line showed increased mRNA levels of MDR1, major vault protein, and MDR-associated protein 1 compared with the parental line, whereas the expression of topoisomerases I, IIalpha, and IIbeta was essentially unchanged, suggesting that XR5944 is susceptible to MDR mechanisms. The median IC90 and IC50 values for XR5944 in tumor-derived cells were 68 and 26 nmol/L, respectively, 6-fold greater than in resistant cell lines. XR5944 was 40- to 300-fold more potent than the other cytotoxics tested, such as doxorubicin, topotecan, and paclitaxel. Breast and gynecologic malignancies were most sensitive to XR5944, whereas gastrointestinal tumors showed greater resistance. A positive correlation (r = 0.68; P < 0.0001) was found between the IC50 values of XR5944 and P-glycoprotein/MDR1 staining but not with either topoisomerase I or IIalpha immunohistochemistry index. These data support the rapid introduction of XR5944 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types, especially ovarian and breast cancer.
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PMID:The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. 1563 57

Idarubicin has been successfully encapsulated in cholesterol-free liposomes, however, little is known about how the rate of drug release from circulating liposomes influences therapeutic activity. The studies described herein assess the attributes of a liposome formulation required to significantly increase the plasma levels of idarubicin and further establish whether increases in the circulation longevity of the drug mediate improved antitumor activity. Pharmacokinetic assessments of 6 different 3[H]-labelled liposome formulations were compared to free idarubicin. The highest idarubicin plasma concentrations were observed with DSPC/DSPE-PEG2000 liposomes formulated with 2 mol% DSPE-PEG2000 and 150 mM (iso-osmotic) internal citrate concentration. It was shown that increased levels of PEG-lipid incorporation augmented IDA release and the optimal liposomal formulation needed to be prepared under iso-osmotic conditions. For efficacy studies in a murine leukemia model, groups of 12-14 mice were treated i.v. with saline or equivalent doses (1, 2, 3 mg/kg) of free or liposomal IDA. Liposomal treatment groups exhibited a higher % increase in life span (ILS) as compared to equivalent doses of free drug. Efficacy studies completed in two drug resistant models, P388/ADR and MDA435LCC6/MDR1, demonstrated that neither the free nor liposomal formulation of idarubicin was therapeutically active. Encapsulation of IDA in liposomes increased antitumor activity in an IDA sensitive model, however, the significant increase in plasma drug levels was not sufficient to overcome multidrug resistance.
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PMID:Substantial increases in idarubicin plasma concentration by liposome encapsulation mediates improved antitumor activity. 1587 92

Drug resistance is the major reason for failure of cancer therapy. When one drug elicits a response in tumour cells resulting in resistance to a large variety of chemically unrelated drugs, this is called multidrug-resistance (MDR). ATP-binding cassette (ABC) transporters contribute to drug resistance via ATP-dependent drug efflux. P-glycoprotein (Pgp) encoded by MDR1 gene, confers resistance to certain anticancer agents. The development of agents able to modulate MDR mediated by Pgp and ABC transporters remained a major goal for the past 10 years. Immunosuppressors, cyclosporin A (CSA) in particular, were shown to modulate Pgp activity in laboratory models and entered very early into clinical trials for reversal of MDR. The proof of reversing activity of CSA was found in phase II studies with myeloma and acute leukaemia. In phase III studies, the results were less convincing regarding the response rate, progression-free survival and overall survival were detected in advanced refractory myeloma. The non-immunosuppressive derivative PSC833 was then extensively studied. This compound shows 10-fold higher potency in reversal of MDR mediated by Pgp. Results from clinical trials with this modulator are still emerging and the notable finding was the need to reduce the dose of anticancer agent used in combination with it. Other effects of CSA and PSC833 on MDR have been described. These two molecules have been shown to have an action on the metabolism of ceramide which stands as second messenger of anticancer agents-induced apoptosis. PSC833 stimulates de novo ceramide synthesis and enhances cell death induced by anticancer agents, such as camptothecins and anthracyclines. In addition, ceramide glycosylation and storage in some cell lines have been described to play a crucial role in resistance to anticancer drugs. CSA is able to inhibit ceramide glucosylation and modulate MDR phenotype. The emergence of other modulators with several ABC protein targets like VX710 are of clinical interest in malignancies expressing several efflux pumps.
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PMID:Immunosuppressors and reversion of multidrug-resistance. 1597 26

Extensive researches have revealed that arsenical can exert anti-tumor efficacy against several kinds of cancers including leukemia. Though, little is known about the effects of arsenical on leukemia resistant to chemotherapy, emerging as a serious clinical problem. In this study, we tested arsenic trioxide (As(2)O(3))-induced apoptosis in K562/ADM multidrug-resistant leukemic cells and investigated its possible mechanisms. Using microscopy, flow cytometry (FCM) and DNA electrophoresis, we found that As(2)O(3) could induce the cells to undergo G2/M phase arrest and apoptosis. Further, it was shown that the levels of FAS and P53 proteins increased and P-glycoprotein (P-gp) decreased upon drug action by employing FCM. Reverse transcription polymerase chain reaction (RT-PCR) detected increased mRNA product of FAS and caspase-3 genes and reduced MDR1 mRNA. CASPASE-3 activity was also enhanced after As(2)O(3) treatment. However, the expression of BCL-2 protein was not affected by the drug. Taken together, As(2)O(3) is able to reverse the apoptosis resistance in drug-resistant K562/ADM cells by modulating expression or activity of key factors associated with apoptosis induction.
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PMID:Arsenic trioxide overcomes apoptosis inhibition in K562/ADM cells by regulating vital components in apoptotic pathway. 1597 94


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