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PubMed2003

Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer.

P-glycoprotein, encoded by the MDR-1 gene, confers multi-drug resistance against antineoplastic agents and is important for the transmembrane transition of various other common therapeutic drugs. Recently, a number of polymorphisms in the MDR-1 gene were identified and the T/T genotype at position 3435 in exon 26 was found to correlate with intestinal P-glycoprotein expression and bioavailability of digoxin after oral administration. We analysed the allelic frequencies at the polymorphic site C3435T in a group of patients with locally advanced breast cancer treated by preoperative chemotherapy to evaluate its predictive value. Sixty-eight patients diagnosed between 1998 and 2001 were treated by preoperative chemotherapy with anthracyclines or these agents combined with taxanes. From genomic DNA, a 106 bp fragment of MDR-1 exon 26 was amplified and the C3435T genotype was determined by Pyrosequencing methodology. A potential correlation with therapeutic response was calculated with Fisher's exact test. The overall clinical response rate (cCR and cPR) was 68% but only 7 patients (10.3%) achieved pathological complete response (pCR). Heterozygous C3435T occurred in 57% of the subjects and 22% of the analysed individuals possessed only T alleles. Statistical analysis revealed a significant correlation (p=0.029) between clinical complete response to preoperative chemotherapy and the T/T genotype. MDR-1 polymorphism C3435T in exon 26 may co-determine resistance to chemotherapy and provide useful information to individualize therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Relationship between multidrug resistant gene expression and multidrug resistant-reversing effect of MS-209 in various tumor cells.

MS-209 is a novel quinoline compound which can overcome multidrug resistance (MDR) both in vitro and in vivo, while having a low level of side effects, and is now being evaluated in a clinical phase II study. Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantitate the expression levels of MDR genes in various mouse and human tumor cell lines. The MDR gene and the beta actin gene, as the internal reference standard, were coamplified separately, and the relative expression of the MDR gene was represented by the MDR/beta actin ratio. The in vitro MDR-reversing effect of MS-209 was then compared with the MDR gene expression (MDR/beta actin ratio). We found a significant correlation between these two parameters. Moreover, a significant correlation was also observed between the level of expression of the MDR1 gene and that of P-glycoprotein in human cell lines. Therefore, the efficacy of MS-209 seems to specifically depend on the level of MDR gene expression (P-glycoprotein). From these observations, it is suggested that RT-PCR assays of MDR1 gene in tumor biopsy specimens might be an effective means to predict the response of tumor cells to combination therapy with MS-209.

Animals↗
PubMedDate not supplied

Expression of the multidrug-resistant gene in human musculoskeletal tumors.

We measured the levels of messenger RNA of the human multidrug-resistant (MDR) gene in 15 human musculoskeletal tumors. In metastatic tumors and those which did not respond to combination chemotherapy, there was an increased expression of this gene. No evidence of expressions of the MDR gene was found in the benign tumors. The high expression of the MDR gene from musculoskeletal tumors apparently induced a multidrug resistance, and this acquired resistance may be due to outgrowth of the P-glycoprotein-expressing MDR tumor. Elucidation of expression of the MDR gene is an important step in malignant musculoskeletal tumors research.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Childhood acute myelogenous leukaemia: association between PRAME, apoptosis- and MDR-related gene expression.

The gene PRAME (preferentially expressed antigen of melanoma) encodes an antigen recognised by autologous cytolytic T lymphocytes. The mRNA level of PRAME is used as a tumour marker due to its overexpression in various malignancies. Furthermore, it is known that the overexpression of genes encoding antiapoptotic proteins leads to the survival of leukaemic cells via exclusion of apoptosis. On the other hand, overexpression of genes encoding ABC transporters may lead to multi drug resistance (MDR). Therefore, we investigated whether there is a relationship between PRAME overexpression and the expression of apoptosis- and MDR-related genes in childhood de novo acute myelogenous leukaemia (AML) patient samples and, furthermore, whether this is a general or an AML-subtype specific event. Microarray analysis and real time quantitative PCR revealed that clinical samples showing PRAME upregulation are associated with a decreasing expression of genes coding for apoptotic proteins and an overexpression of genes encoding ABC transporters. Our results indicate that patients showing PRAME upregulation may have an increased risk of MDR induction.

Acute Disease↗
PubMed1990

Expression of a multidrug resistance gene in esophageal adenocarcinoma. Correlation with response to chemotherapy and comparison with gastric adenocarcinoma.

The resistance of malignant tumors to chemotherapy is often associated with overexpression of the multidrug resistance gene MDR. Its gene product, P-glycoprotein, acts as a drug efflux pump for chemotherapeutic agents. The authors studied MDR expression in 28 adenocarcinomas arising in Barrett's esophagus (EAs) using a monoclonal antibody directed against this gene product. The results were compared with MDR expression in 27 gastric adenocarcinomas (GAs). P-glycoprotein was detected in both tumor and normal mucosa in 7 of 27 GAs and in 6 of 10 EAs that were resected without prior chemotherapy. Chemotherapy was given before surgical resection in 18 of the EAs studied. Five patients had a partial response to chemotherapy, and one had a complete eradication of his carcinoma; all of these tumors were negative for P-glycoprotein. Of 12 patients without chemotherapy response, 6 had tumors that expressed P-glycoprotein. The authors conclude that P-glycoprotein is present in EAs and GAs before exposure to chemotherapy. The presence of P-glycoprotein in tumors usually correlates with its presence in the adjacent mucosa. Its presence in tumor cells may be an indicator of lack of sensitivity to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Expression of the mdr3 gene in prolymphocytic leukemia: association with cyclosporin-A-induced increase in drug accumulation.

Typical multidrug resistance in human and animal cell lines is caused by overactivity of an unidirectional transmembrane drug efflux pump, encoded by the MDR genes, called mdr genes in mice and humans and pgp genes in hamsters. In humans, two mdr genes, mdr1 and mdr3, with approximately 80% nucleotide homology, have been identified. There is increasing evidence that overexpression of the mdr1 gene plays a role in resistance to anticancer agents in specific tumor types. However, currently no data are available on a possible role for mdr3 in drug resistance. Here we report high levels of expression of mdr3 gene sequences in leukemic cells from 6 out of 6 patients with prolymphocytic leukemia (PLL). No mdr1 expression was detected in 5 out of 6 of these samples, whereas a low level of mdr1 expression was found in a sample from one PLL patient in the course of transformation to non-Hodgkin's lymphoma. Except for this patient, all other PLL cases studied had not received prior chemotherapy. In vitro drug uptake studies showed that daunorubicin accumulation in PLL cells was increased by cyclosporin A. Since cyclosporin A is an inhibitor of the mdr1-encoded P-glycoprotein drug pump, these data suggest that in PLL cells mdr3 also codes for a drug efflux pump. Our findings could partly explain the primary refractoriness of PLL to chemotherapy.

Adult↗
PubMed1990

[Regulation of the multidrug resistance (MDR)1 gene expression].

MDR1 gene encodes a gp-170 membrane protein which acts as a energy-dependent pump to transport anticancer agents out of the cells. In this article, we briefly summarize the MDR gene family, gene amplification, gene expression by differentiation and gene expression in clinical tumors. We also describe the characterization of the promotor and tissue specific enhancer of the MDR1 gene and our recent study of the regulatory mechanism of this gene expression.

Antineoplastic Agents↗
PubMed1991

Regulation of 2-acetylaminofluorene-and 3-methylcholanthrene--mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver.

Previous studies by this laboratory have indicated that expression of the multidrug resistance (mdr) gene can be increased in vivo by exposure to a variety of xenobiotics. Because of the nature of these compounds, it was proposed that mdr gene expression might, at least in part, be regulated by the arylhydrocarbon (Ah) receptor. In the present study, we used a primary hepatocyte culture model to examine the relationship between induction of cytochrome P450IA and mdr expression in vitro. Both 3-methylcholanthrene (MC) and 2-acetylaminofluorene (AAF) were efficient inducers of mdr expression in this model. Induction of mdr gene expression by both MC and AAF obeyed a log10 concentration/response relationship. In contrast, 2,3,7,8-tetrachlorodibenzo-P-dioxin did not induce mdr expression at concentrations that yielded maximum induction of cytochrome P450IA expression. These data suggest that mdr induction was not mediated via the Ah receptor. Nuclear run-off analysis indicated that both AAF and MC induced mdr expression by increasing transcription. Primer extension analysis indicated that mdr gene transcription was initiated at one major site 151 bp upstream of the ATG site in both the uninduced and induced state in vivo and in vitro. The sequence of the primer and the site of initiation of gene transcription indicate that the main gene induced was the mdr 1b gene.

2-Acetylaminofluorene↗
PubMed1990

Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus.

The multidrug resistance (mdr) gene family has been shown to encode a membrane glycoprotein, termed the P-glycoprotein, which functions as a drug efflux pump with broad substrate specificity. This multigene family is expressed in a tissue-specific fashion in a wide variety of normal and neoplastic tissues. The regulation of mdr gene expression in normal tissues is not understood. We have recently shown that mdr mRNA and the P-glycoprotein increases dramatically in the secretory luminal and glandular epithelium of the gravid murine uterus. This observation has suggested that mdr gene expression in the uterus is controlled by the physiologic changes associated with pregnancy. This report now demonstrates that mdr mRNA and P-glycoprotein are induced at high levels in the uterine secretory epithelium by the combination of estrogen and progesterone, the major steroid hormones of pregnancy. This regulation of mdr gene expression in the uterus does not require any other contribution from the fetus or placenta. The data indicate that this gene locus is hormonally responsive to estrogen and progesterone in the uterine secretory epithelium, suggesting an important and physiologically regulated role during pregnancy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Application of SPET using technetium-99m sestamibi in brain tumours and comparison with expression of the MDR-1 gene: is it possible to predict the response to chemotherapy in patients with gliomas by means of 99mTc-sestamibi SPET?

Technetium-99m sestamibi (MIBI) is thought to be passively taken up by metabolically active tumour cells and effluxed from them by P-glycoprotein (Pgp). This 170-kDa membrane-bound protein, encoded by the MDR-1 gene, acts as an energy-dependent efflux pump for several antineoplastic agents, resulting in multidrug resistance. For this reason, it is of interest whether the tumour's response to chemotherapy can be predicted by MIBI single-photon emission tomography (SPET). In this study, MIBI SPET was compared with thallium-201 (Tl) SPET using magnetic resonance imaging as a guide in 16 patients with untreated brain tumours [ten glioblastomas (GBs), two anaplastic astrocytomas (AAs), two low-grade gliomas (LGASs) and two metastatic brain tumours) and in four patients who had received treatment for with brain tumours (two GBs, two AAs). In addition, we investigated the expression of the MDR-1 gene and its product Pgp in the same patients, and compared the results with MIBI SPET findings. MIBI, as well as Tl, was highly accumulated and retained in the enhanced region of malignant gliomas. In addition, MIBI SPET yielded sharp and well-contrasted images, and the margin of the tumour was more clearly defined than with Tl SPET due to a good signal-to-noise ratio. Follow-up MIBI SPET in patients who had received therapy showed marked uptake in a patient with malignant transformation, who deteriorated clinically. Patients with no uptake on MIBI SPET showed no sign of recurrence. Semiquantitative analysis of untreated patients showed a relationship between the early uptake index (UI, ratio of average count/pixel in the lesion to that in the contralateral area on early images) and the degree of malignancy (early UI = 1.08+/-0.06 in LGASs, 4.10+/-0.84 in AAs, 5.71+/-3.47 in GBs, and 7.52+/-1.52 in metastatic brain tumours). The retention index (RI, ratio of delayed to early UI) of MIBI was significantly lower than that of Tl in metastatic brain tumours (P<0.05), but not in malignant gliomas. Histological and biological investigation of gliomas showed that the MDR-1 gene and its product Pgp were expressed only in normal endothelial cells and not in tumour cells or proliferating endothelial cells; Pgp tended to decrease as the degree of malignancy rose. Hence, the presence of Pgp and the grade of malignancy were inversely related in gliomas. By contrast, immunohistochemical study showed strong accumulation of Pgp in metastatic brain tumour cells. These histopathological findings and MIBI SPET findings are compatible with experimental data; MIBI was washed out by Pgp. The main cause of chemoresistance is probably not an increasing drug efflux by Pgp in gliomas. Thus, MIBI SPET is useful for detecting the active lesions, but may not be useful for predicting the response to chemotherapy in gliomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

An electrophoretic molecular karyotype of a clinical isolate of Aspergillus fumigatus and localization of the MDR-like genes AfuMDR1 and AfuMDR2.

The molecular karyotype of a clinical isolate of Aspergillus fumigatus (10AF/86/10) was determined by contour-clamped homogeneous electric field gel electrophoresis. Five chromosomal bands were resolved by this method. The resolved chromosomes ranged in size from 1.7 to 4.8 Mb, and together constituted a total genomic size of at least 15.8 Mb. Southern analysis of the separated chromosomes located the position of two MDR-like genes, AfuMDR1 and AfuMDR2, on chromosomes III and IV, respectively. The methods described herein may enable the application of molecular karyotyping of A. fumigatus in epidemiologic surveillance studies.

Aspergillosis↗
PubMed1998

A unique interaction between polyamine and multidrug resistance (P-glycoprotein) transporters in cultured Chinese hamster ovary cells transfected with mouse mdr-1 gene.

We have shown that a functional link exists between the polyamine transporter and the multi-drug resistance (MDR) efflux transporter (P-glycoprotein, P-gp) in MDR-positive cancer cells. To further explore the nature of this interaction, we have examined the effect of reduced polyamine transport activity on cellular expression and activity of P-gp acquired by either selection or transfection. Chinese hamster ovary (CHO) cells and their polyamine transport-deficient mutants (CHOMGBG) were transfected with mouse mdr-1b gene. The activity of P-gp in these cells was quantified by measuring cellular accumulation of radiolabeled taxol and etoposide in the presence and absence of the P-gp modulator SDZ PSC-833 (valspodar; a semisynthetic undecapeptide derived from cyclosporin D). The mdr-1b-transfected CHO cells accumulated 2- to 3-fold less taxol and etoposide than the controls, an accumulation defect reversed by the potent MDR modulator PSC-833. Despite expression of P-gp on the surface of mdr-1b-transfected CHOMGBG cells, this classic MDR phenotype was not observed. Similarly, CHO cells, but not CHOMGBG cells, showed MDR activity after selection with doxorubicin as determined by reduced accumulation of radiolabeled taxol. Treatment with 50 microM of reduced polymer of spermine and glutaraldehyde, a selective blocker of the polyamine transport system, reduced MDR activity in mdr-1-transfected CHO cells and restored cellular accumulation of etoposide and taxol to control levels, effects not observed in mdr-1-transfected CHOMGBG cells. Notably, mdr-1-transfected CHO cells were 4- to 16-fold more resistant to the cytotoxic effects of the P-gp substrates doxorubicin, taxol, and etoposide than were the mdr-1-transfected CHOMGBG cells. CHO cells transfected with the mdr-1 gene exhibited a 23% reduction in cellular uptake of [14C]spermidine compared with untransfected controls; spermidine accumulation in CHOMGBG cells was no different than that in untransfected controls. These data suggest that the existence of a functioning polyamine transport system may be a requirement for MDR transporter activity, while the expression of functioning P-gp appears to reduce polyamine transporter activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

High cell density-dependent resistance and P-glycoprotein-mediated multidrug resistance in mitoxantrone-selected Chinese hamster cells.

Mitoxantrone (MIT) resistance has been studied in a colony selected from the CHO AA8 parental line in one step under a low degree of selective pressure (9 nM). The cells of the clonal isolate AA8/MIT C1(0) were sensitive to 9 nM MIT at low cell density but able to grow at high density. Parental AA8 cells were not able to grow under the latter condition. Decreased MIT accumulation (-20%) was observed at this step (step 0) in the absence of overexpression of mdr RNA coding for the drug efflux pump P-glycoprotein. Furthermore, AA8/MIT C1(0) did not exhibit cross resistance to vincristine, Adriamycin and etoposide at low cell density. During subsequent controlled growth for 2 months at high cell density in the presence of 9 nM drug, an additional selection occurred leading to a 4-fold MIT-resistant subline AA8/MIT C1(+). This subline was characterized at this step (step I) and after an additional 4 months of culture in the presence of 9 nM MIT (step II). Analysis of mdr gene expression and gene copy number showed an increase in mdr RNA and a pattern of mdr gene amplification which changed between step I and II. AA8/MIT C1(+)II exhibited a classical multidrug resistance phenotype with decreased accumulation of [14C]MIT and cross-resistance to vincristine, Adriamycin and etoposide. The ability to form the cleavable complex in the presence of etoposide in DNA topoisomerase II-containing nuclear extracts was identical in AA8/MIT C1(+)II and AA8 cell lines. These results demonstrate a new sequence of events in MIT resistance: low level of drug resistance at high cell density followed by mdr gene amplification.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Bcl-2 and mdr-1 gene expression during doxorubicin-induced apoptosis in murine leukemic P388 and P388/R84 cells.

The induction of apoptosis by doxorubicin (DOX) alone or in the presence of efflux blockers, verapamil (VPL) or trifluoperazine (TFP), and of bcl-2 and mdr-1 gene expression was analyzed in murine leukemic P388 and doxorubicin resistant P388/R84 cells. Incubation with DOX (0.1-1 microM) for 24 hours induced apoptosis in sensitive cells but not in the resistant P388/R84 cells. Flow cytometric analysis of apoptosis by terminal dideoxynucleotidyl (TdT) assay showed that 1 microM DOX induced apoptosis in 70% of P388 cells and in less than 5% of P388/R84 cells. When P388/R84 resistant cells were co-incubated with DOX and efflux blockers (10 microM VPL or 15 microM TFP), enhanced cellular DOX accumulation was accompanied by apoptosis. Quantitative analysis of DNA fragmentation by 14C-thymidine incorporation and gel electrophoresis of fragmented DNA confirmed the results from TdT assay and showed enhancement of DOX-induced DNA fragmentation in the presence of efflux blockers (VPL or TFP). DOX + VPL and DOX + TFP combination treatments induced apoptosis in upto 55% and 83% of P388/R84 cells, respectively. mdr-1 mRNA and P-gp expression were not altered during DOX-induced apoptosis. The results suggest that in murine leukemic cells, down-regulation of bcl-2 mRNA expression occurs during DOX-induced apoptosis and it depends on the cellular drug retention determined by mdr-1/P-gp drug efflux.

Animals↗
PubMed1995

Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy.

PURPOSE: Overexpression of the multidrug resistance gene (mdr-1) is present in up to 60% of relapsed lymphomas. To study its role in lymphomas, we conducted a controlled trial of dexverapamil, an inhibitor of the mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS: Eligible patients had recurrent Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stable tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR). RESULTS: Of 154 patients entered onto the trial, 109 had NHL and 45 had HD. The median age was 44 years, 67% had stage IV disease, and the median number of prior regimens was two (range, one to 12) in NHL and one (range, one to four) in HD. Sixty-four patients (42%) crossed over, of which eight were not assessable. The maximum-tolerated dose of dexverapamil was 900 mg/m2/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs. The mdr-1 level was measured in 44 biopsies from 19 patients. Pretherapy, mdr-1 was low (median, 2.5 U) but increased (median, 12.2 U) at crossover. Of six patients with mdr-1 levels greater than 15 U, three responded to dexverapamil, while only one of eight patients with mdr-1 levels less than 15 U responded. EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity. CONCLUSION: These results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pgp are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier intervention with dexverapamil may be more effective and warrants further study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

p53 may mediate the mdr-1 expression via the WT1 gene in human vincristine-resistant leukemia/lymphoma cell lines.

To investigate the regulatory mechanism of the expression of the multidrug resistance gene (mdr-1) and the multidrug resistance-associated protein gene (mrp), we investigated if p53, WT1, RB, C-myc, N-myc, cyclin D1, p16INK4 (p16) are involved in the acquirement of multidrug resistance phenotype (MDR) in human vincristine (VCR)-resistant cells of leukemia/lymphoma cell lines. By using RT-PCR, we observed that MDR in VCR-resistant cell lines was mediated by either mdr-1 or mrp genes. In cells that acquired the overexpression of mdr-1, downregulation of p53 and upregulation of WT-1 were observed. In contrast, no constant change of genes was observed in cells that overexpressed mrp. Although the change in the expression level of cyclin D1 and p-16 accompanied the development of VCR resistance, the mRNA of RB, C-myc and N-myc showed no correlation with the degree of VCR resistance or the level of mdr-1 expression. These results may provide a plausible diagnostic marker for determination of drug sensitivity in cancer patients and suggest that p53 may mediate directly or indirectly the expression of mdr-1 via WT1 in VCR-resistant hematologic cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

The P-glycoprotein multidrug transporter.

1. P-glycoprotein (P-gp) is a transmembrane protein involved in ATP-dependent efflux of various structurally unrelated anticancer drugs. Its overexpression in cancer cells decreases intracellular drug concentrations and, thus, confers a multidrug resistance phenotype. 2. P-gp is encoded by MDR genes, which constitute a small gene family comprising two genes in humans and three genes in rodents. Only the MDR1 gene in humans and mdr1 and mdr3 genes in rodents have been demonstrated to be involved in drug resistance. 3. P-gp encoded by the human MDR1 gene is a phosphorylated and glycosylated protein 1289 amino acids long, and consists of 2 halves that share a high degree of similarity. 4. A wide variety of cancers have been shown to express P-gp, including solid tumors and hematological malignancies. This P-gp positivity can be evidenced at the time of diagnosis prior to chemotherapy or at relapse after treatment, and has been correlated with treatment failure and poor prognosis in several types of cancer. In addition, P-gp is also expressed by some normal tissues, such as liver and kidney. 5. P-gp expression is regulated by various factors, including xenobiotics and hormones. 6. P-gp-mediated multidrug resistance can be reversed by various unrelated compounds called chemosensitizers or reversing agents. These drugs act through inhibition of P-gp function and have entered clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗