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

In an attempt to identify the target protein, P-GP or mrp, of each MDR antagonist, verapamyl (Ver), dipyridamole (Dip), or cyclosporin A (Cy-A), this study was designed to compare the activity of the three afore-mentioned drugs and to test their combined effect on the cidal activity of vincristine (VCR) in five types of wild and the corresponding VCR-resistant cultured cell lines from human leukemia and lymphoma. Three of the VCR-resistant cell lines are characterized by the overexpression of mdr-1, while two cell lines overexpress mrp. We found that all three antagonists additively to synergistically enhanced the cidal activity of VCR for the five wild-type and VCR-resistant cell lines in a dose dependent manner when used singly. Combinations consisting of a 20% inhibitory concentration (IC20) of VCR plus two antagonists also showed additive to synergistic effects on both wild and VCR-resistant cell lines. It is of interest that the combined effect of IC20 VCR plus MDR antagonists on the three VCR-resistant cell lines expressing mdr-1 was significantly superior to those of the two cell lines expressing the mrp gene. These results suggest that the combined effect of MDR antagonists work better than their single use and that the MDR antagonists work more efficiently in cells showing drug resistance through mdr-1 than in those utilizing mrp.
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PMID:Effect of MDR antagonists on the cidal activity of vincristine for cells expressing MDR-1 is superior to those expressing MRP. 966 31

The aim of the study was to investigate whether 99Tc(m)-MIBI (Cardiolite), recently shown to be a substrate for P-glycoprotein, has the potential to be used as a marker for mdr1 gene expression and whether cyclosporin A (CyA) can modify its accumulation in vivo. Leukaemic cells from ten patients with acute myelocytic leukaemia (AML) were used, five with undetectable mdr1 gene expression and five with mdr1 mRNA levels ranging from 1.0 to 3.8 mdr1 mRNA transcripts per cell. Cells were incubated with 99Tc(m)-MIBI, or with daunorubicin (Dnr), with and without 3 microM CyA. The median 99Tc(m)-MIBI accumulation (% of added radioactivity) in mdr1-negative cells was 0.89% and in the mdr1-positive cells 0.34%, P = 0.01. In mdr1-negative cells, the median increase in 99Tc(m)-MIBI accumulation with CyA was 30% compared with the mdr1-positive cells with a median increase of 242%, P = 0.009. CyA had no significant effect on Dnr accumulation in four of the mdr1-negative samples. The median increase of Dnr accumulation in the mdr1-positive cells was 40%. The results show that 99Tc(m)-MIBI with a high sensitivity can detect rather low levels of mdr1 gene expression in clinical samples. Consequently, 99T(c)m-MIBI scintigraphy has the potential to be used for monitoring the effect of resistance modifiers on the accumulation and retention of cytostatic drugs in human tumours in vivo.
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PMID:Multidrug resistance phenotype in leukaemic cells from patients with acute myelocytic leukaemia can be detected with 99Tc(m)-MIBI. 966 40

Leukemia/lymphoma cells, clinically refractory to therapy are often associated with expression of P-glycoprotein (P-gp), which is encoded by the multidrug resistance (MDR) gene, mdr1. Cell lines expressing mdr1 exhibit resistance to several structurally unrelated lipophilic drugs, such as anthracyclines, vinca alkaloids, and epopodophyllotoxins. This MDR can be conferred to drug-sensitive cells mdr1 cDNA transfer. In resistant cells, MDR is characterized by overexpression of P-gp and by the enhanced efflux, and P-gp fluorescence probe, rhodamine 123 (Rh 123). This can be circumvented by addition of certain non-cytotoxic drugs, such as verapamil and cyclosporin A.
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PMID:The multidrug resistance in human leukemias. Minireview. 968 82

We studied the effect of thioacridine derivatives on the function of P-glycoprotein in MDR mouse T-lymphoma cell line L5178 and in MDR human leukemia cell line K562/ADR by rhodamine 123 uptake assay. The effect of some selected thioacridines was also investigated on the expression of the mdr1 gene. Expression was analysed by RT-PCR. Two compounds: 3-amino-9-thio-(4'-nitrobenzyl)acridinone and 2,7-dimethoxy-9-thio-(2'-diethylaminoethyl) acridinone were able to block the function of the P-gp, and also to decrease significantly mdr1 gene expression. Because these two derivatives exert their positive effects as reversing agents they could be potential candidate anticancer agents for further investigation. The thioacridines, which do not affect P-gp function, do not affect or increase the expression of mdr1 gene. Our results showed the structure-activity relationships of these compounds, providing a direction for the development of new, more active compounds.
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PMID:Effect of new thioacridine derivatives on P-gp function and on mdr1 gene expression. 971 9

Overexpression of the trans-membrane drug efflux pump P-glycoprotein is one of the major mechanisms by which cancer cells develop multidrug resistance. We demonstrated previously that noncytotoxic doses of various genotoxic chemicals, particularly DNA cross-linking agents, preferentially altered expression of inducible genes. These effects occurred principally at the transcriptional level and were closely correlated temporally with DNA damage. Because the mdr1 gene coding for P-glycoprotein has been reported to be highly inducible, we were interested in the effects of genotoxic cancer chemotherapy agents on its expression. We report that the DNA cross-linking agent mitomycin C significantly suppressed mRNA and protein expression of P-glycoprotein and decreased the rate of drug efflux. Mitomycin C pretreatment also significantly increased the sensitivity of cancer cells to subsequent killing by the P-glycoprotein substrate doxorubicin, decreasing the ED50 by 5- to 10-fold. Suppression of P-glycoprotein expression was also observed with subtoxic doses of the DNA cross-linking agents cisplatin, BMS181174, and chromium(VI). These effects occurred in both human and rodent cell lines; in cell lines derived from colon, breast, leukemia, neuroblastoma, and hepatoma tumors; and under both monolayer and "spheroid" culture conditions. These results suggest the basis for novel clinical cancer chemotherapy regimens aimed at drug-resistant tumors, in which a sub-chemotherapeutic dose of a DNA cross-linking agent is used to modulate the multidrug resistance phenotype prior to treatment with a second cytotoxic agent.
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PMID:Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents. 981 17

Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.
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PMID:PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein. 981 80

Various gene alterations are involved in the drug resistance of leukemia cells. To understand the mechanism that underlies the emergence of cells with such gene alterations in human leukemia, we performed clonal analysis of the gene expression of mutant dihydrofolate reductase (DHFR) and mdr1 in trimetrexate-resistant human leukemia MOLT-3 cells. Trimetrexate-resistant (70- and 60-fold) sublines were developed in the presence or absence of an exogenous supply of thymidine (MOLT-3/TMQ70/Th+, MOLT-3/TMQ60/Th-, respectively). Ten clonal lines were isolated by methyl cellulose cloning from each of the 2 trimetrexate-resistant MOLT-3 sublines. All the clonal lines from the 2 sublines expressed mutated DHFR mRNA, with a base change (T --> C) at the second position of codon 31, as well as the wild-type mRNA, in accordance with cross-resistance to methotrexate. On the other hand, mdr1 mRNA expression was demonstrated by reverse-transcription polymerase chain reaction only in clonal lines from MOLT-3/TMQ70/Th+ cells. mdr1 mRNA expression in clonal lines from MOLT-3/TMQ70/Th+ cells and subclonal lines subsequently obtained from the 3 clonal lines with different mdr1 mRNA expression levels was heterogeneous, and its high expression levels were correlated with acquisition of the multidrug resistance (MDR) phenotype. Polymerase chain reaction-based assay for separate microsatellites, mfd27 and mfd41, demonstrated genomic instability among clonal and subclonal lines of MOLT-3. The clonal analysis of polymorphic microsatellites also suggested that emergence of MDR in trimetrexate-resistant MOLT-3 cells in thymidine was not only heterogeneous but also progressively expanding among clones. Genomic instability may play a role in the establishment and clonal evolution of drug resistance in leukemia cells.
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PMID:Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA expression in trimetrexate-resistant human leukemia MOLT-3 cells developed in thymidine. 1036 Aug 22

Expression of the mdr1 (multidrug resistance), mrp (multidrug resistance associated protein), and lrp (lung resistance related protein) genes is associated with transport related MDR (multidrug resistance). We quantified mRNA levels of these genes using competitive reverse transcription polymerase chain reaction (RT-PCR) in 128 samples of leukaemic cells from 92 patients with acute myelogenous leukaemia (AML). There was a wide variation between the samples in mRNA levels of all three genes. The mean mdr1 mRNA level was 1.3 transcripts per cell (range undetectable to 15.8), the mean mrp level was 7.9 (range 0.1-36.2) and mean lrp 3.9 (range 0.1-29). Lrp mRNA levels were higher in samples drawn at diagnosis from the 15 patients with resistant disease than from the 37 with chemosensitive disease (4.9 SD 3.1 v 2.9 SD 2.3, P = 0.016). Neither mdr1 nor mrp mRNA levels were predictive for response to chemotherapy. In samples from patients who had received chemotherapy, those that had received mitoxantrone (n = 24) had higher lrp mRNA levels (mean 4.8, SD 2.5) than those that had not (n = 20, mean 2.8, SD 2.4, P = 0.012). In conclusion, the results indicate that lrp expression is associated with inferior response to chemotherapy in AML and that lrp expression increases after exposure to mitoxantrone.
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PMID:High levels of lung resistance related protein mRNA in leukaemic cells from patients with acute myelogenous leukaemia are associated with inferior response to chemotherapy and prior treatment with mitoxantrone. 1046 50

This study demonstrates that astemizole, a non-sedating anti-histaminergic drug with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of doxorubicin in doxorubicin-resistant human leukemia cells (K562/DXR). Astemizole synergistically potentiated the cytotoxicity of doxorubicin for K562/DXR cells at a concentration of 0.1-3 microM in a dose-dependent manner, whereas they showed hardly any synthergistic effect in the parental cell line (K562) at the same concentration. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycoprotein, we evaluated the effect of astemizole on P-glycoprotein activity in cytofluorographic efflux experiments with doxorubicin. Our results indicate that astemizole inhibits the P-glycoprotein pump-efflux activity in a dose-related manner. Moreover, it also inhibits the photolabeling of P-glycoprotein by [3H]azidopine in a dose-dependent manner. These findings provide a biological basis for the potential therapeutic application of astemizole as an anticancer drug either alone or in combination with doxorubicin to multidrug-resistant leukemic cells.
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PMID:Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole. 1070 23

Mutations in ras genes have been found to be the most frequent genetic aberrations in adult myeloid leukaemia (AML). Some reports have shown an improved outcome of ras-mutated AML. In order to understand the biology of ras mutation in AML, we studied a cohort of patients treated in a prospective multicentre trial for ras mutational status and resistance gene expression. Blast samples from 162 adult patients with de novo or secondary AML were examined for resistance gene expression (mdr1, mrp1 and lrp) and ras mutations using reverse transcription-polymerase chain reaction and protein nucleic acid-competitive polymerase chain reaction strategies respectively. Ras mutations were confirmed using DNA sequencing. Ras mutations leading to an exchange of amino acids were found in 40 (25%) patients. Thirty AML patients had N-ras mutations and nine patients had K-ras mutations. One patient showed both N-ras and K-ras mutations. Resistance gene expression was positive for mdr1 in 30%, for mrp1 in 43% and for lrp in 62% of patients. There was a strong inverse correlation between the presence of ras mutation and mdr1 expression (P = 0.005). However, no significant difference was seen between patients with or without ras mutations and mrp1 or lrp expression. Whereas mdr1 expression was associated with a lower complete remission rate (P < 0.04), ras mutations had no significant influence on remission status. Neither ras mutation nor mdr1 expression had a significant impact on overall or disease-free survival to date. For the first time, there is evidence that activated ras genes are associated with lower mdr1 expression in AML.
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PMID:Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. 1116 22


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