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PubMed1991

Amplification and expression of mdr genes and flanking sequences in verapamil hypersensitive hamster cell lines.

The properties of several multidrug resistant (MDR) Chinese hamster ovary (CHO) cell lines which are verapamil hypersensitive have been investigated, extending our earlier study of two such cell lines. It was observed that increasing levels of multidrug resistance are associated with increasing verapamil and nicardipine sensitivity, although the cell lines are not hypersensitive to cyclosporin A. Although there is appreciable amplification of the P-glycoprotein gene at higher levels of multidrug resistance/verapamil hypersensitivity, there is only very low or no amplification of five flanking genes, including the sorcin gene. Low levels of resistance (3-10 fold) appear to involve increased P-glycoprotein gene expression at the level of transcription. P-glycoprotein levels of the cell lines have been measured by flow cytometry using the monoclonal antibody C219, and there is a general correlation between P-glycoprotein overexpression, increased levels of the corresponding mRNA and the level of verapamil hypersensitivity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Retroviral mediated transfer of the human multidrug resistance gene (MDR-1) into hematopoietic stem cells during autologous transplantation after intensive chemotherapy for metastatic breast cancer.

Patients with metastatic breast cancer will receive 4-5 cycles of induction chemotherapy on one of the ongoing Medicine Branch protocols. Patients achieving at least a partial response, and who do not have evidence of bone marrow involvement and who do not have metastatic bone disease, will undergo PBSC and bone marrow harvest when hematologic recovery has occurred. Patients who have not achieved a PR, but who are responding to therapy, may be treated with additional cycles of therapy in an attempt to achieve a PR. Such patients will be eligible for transplant if a PR is obtained. 70% of the bone marrow and PBSC will be cryopreserved. The CD34+ subpopulation from the remaining 30% of the bone marrow and PBSC harvest will be obtained using an anti-CD34+ antibody and immunoabsorption column. The bone marrow and peripheral blood CD34 cells will be transduced with a retroviral vector expressing the human MDR-1 cDNA. Patients with positive bone scans or histologic evidence of bone marrow involvement will be excluded from the gene transfer component of the protocol. The MDR-1 transduced CD34 cells will be reinfused along with the non-transduced bone marrow and PBSC into patients following high dose ICE chemotherapy. Serial peripheral blood and bone marrow samples will be obtained to study hematopoietic reconstitution with MDR-1 transduced cells. Patients with residual or progressive disease after ABMT will be treated with taxol or vinblastine. In these relapsed patients, peripheral blood and bone marrow samples will be obtained to study whether chemotherapy amplifies the proportion of hematopoietic cells containing the MDR-1 provirus. We will monitor the nadir blood counts of each patient receiving salvage chemotherapy for evidence of myeloprotection and correlate this data with changes in the mean proviral copy number. Sites of relapsed tumor will be biopsied to test for the presence of the MDR-1 provirus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

[The relationship between abnormal MDR gene expression and chemotherapy response in lymphoid malignancies].

OBJECTIVE: To investigate the expression of multidrug resistance-1 (MDR(1)), Topoisomerase II (Topo II), glucocorticoid receptor (GCR) and their correlation with relapse rate and chemotherapy response in lymphoid malignancies. METHODS: The expression of MDR(1), Topo II and GCR in 189 patients with lymphoid neoplasms was examined by RT-PCR, slot blot and ligand-labelled methods. RESULTS: (1) The expressions of MDR(1), Topo II, GCR in untreated and relapsed/refractory patients with ALL, NHL, NHL-L, MM were significantly abnormal at varying levels, especially in the relapsed/refractory group. (2) The complete remission (CR) rate of MDR(1) high expression group (MDR(1)(+)) was significantly lower than that of MDR(1) negative expression (MDR(1)(-)) group (P < 0.05), and the relapse rate of MDR(1)(+) group was significantly higher than that of MDR(1)(-) group (P < 0.05). In untreated patients, the relapse rate in the Topo II low expression (Topo II(-)) group was positively higher than Topo II high expression (Topo II(+)) group (P < 0.05), whereas in the relapsed/refractory patients, the CR rate of Topo II(-) group was significantly lower than that of Topo II(+) group (P < 0.05). In the untreated and relapsed/refractory patients, the CR rates of low GCR expression (GCR(-)) group was obviously lower than that in the normal GCR expression group (P < 0.05). (3) Considering mono-drug resistance mechanism, CR rate of MDR(1)(+) group was the lowest, Topo II(-) group took the second place and GCR(-) group was the highest. As multiple drug resistance mechanisms coexisted, the CR rate of MDR(1)(+) + Topo II(-) + GCR(-) group and MDR(1)(+) + Topo II(-) group (11.1% and 15.4%, respectively) were significantly lower than that of MDR(1)(+), Topo II(-) and GCR(-) group (36.7%, 48.0% and 53.8%, respectively; P < 0.05 - P < 0.001). CONCLUSION: There are primary and acquired drug resistance in lymphoid neoplasms. The high expression of MDR(1), low expression of Topo II and GCR are positively related to low chemotherapy response rate and high 2-year relapse rate. Co-analysis of MDR(1), Topo II and GCR may play an important role on chemotherapy response and prognostic judgment in lymphoid neoplasms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Multidrug resistance gene (MDR 1) expression in neuro-axial tumours of children and young adults.

Drug resistance in many cancers outside the CNS has been associated with over-expression of the multidrug resistance gene (MDR1), which codes for the transmembrane efflux pump P-glycoprotein (Pgp). To determine whether tumours of the neuroaxis over-express MDR1 and to identify the site of Pgp expression we examined 50 tumour specimens from 46 children and young adults using immunocytochemistry. Pgp was not expressed by any neoplastic cells, but was detected in the endothelium of tumour blood vessels in 35 of the 50 samples (70%). 11/35 (31%) were Pgp positive in the majority of vessels, 11/35 (31%) in a proportion, but < 50% of vessels, and 13/35 (37%) in one or two vessels. Pgp was also detected in surrounding normal brain capillaries. MDR1 may play a role in the chemoresistance of neuro-axial tumours either by its expression in the normal blood-brain barrier or by forming a blood-tumour barrier. The proportion of vessels expressing Pgp may determine the degree of resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Criteria of measuring mdr-1 gene expression level in breast cancer by RT-PCR].

OBJECTIVE: To formulate criteria of judjing multidrug resistance gene(mdr-1 gene) expression level and to provide basis for predicting chemotherapy response and prognosis. METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) assay, the expression of mdr-1 gene in 82 breast cancer samples was detected. The data were treated by statistic analysis system (SAS)-singlevariate analysis. RESULTS: The level of mdr-1 gene expression clearly deviated from normal to right distribution (P < 0.0001), and thus might be divided by quantiles P50(mdr-1/beta 2-MG = 0.2) and P75 (mdr-1/beta 2-MG = 0.6), which were taken as the criteria for comparing 56 patients' chemosensitivity to ADM, VDS, VCR in vitro and 32 relapsed metastatic patients' chemotherapy response in vivo, seperately. When mdr-1/beta 2-MG < 0.2, the ratio of coincidence was lower between expression of mdr-1 and drug resistance in vitro and in vivo; When mdr-1/beta 2-MG > or = 0.2-< 0.6, the ratio of coincidence elevated slightly, but in 30%-50% of the cases drug resistance in vitro and in vivo did not correlate. When mdr-1/beta 2-MG > or = 0.6, the ratio of coincidence elevated significantly. According to the above-mentioned results, criteria of evaluating mdr-1 gene expression level was formulated: the mdr-1/beta 2-MG ratio < 0.2(P50) was considered as negative expression, the ratio > or = 0.2-< 0.6(P75) was weakly positive expression, > or = 0.6 was strongly positive expression. CONCLUSIONS: The criteria of mdr-1 gene expression may reflect objectively drug resistance in vitro and chemotherapy response in vivo. The method may also be applicable to other tumours.

Antineoplastic Agents↗
PubMed1993

Multidrug resistance (MDR) genes in haematological malignancies.

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistant in vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents.

Acquired resistance to multiple natural products in vitro is mediated by P-glycoprotein (Pgp). Expression of this protein has been demonstrated in some normal tissues and in tumor samples obtained from both untreated and treated patients. In situ hybridizations with RNA probes have demonstrated higher levels of expression of mdr-1/Pgp in well-differentiated tumors and in well-differentiated areas in tumors with mixed histologies. Expression of mdr-1/Pgp in human colon carcinoma cell lines was increased by the differentiating agents sodium butyrate, dimethyl sulfoxide, and dimethylformamide. In the SW-620 cell line addition of sodium butyrate resulted in a rapid induction of mdr-1/Pgp mRNA that was sustained for the duration of the exposure. The levels of P-glycoprotein were measured by immunoblotting and were also increased. Similar results were obtained in three other cell lines including the HCT-15 line. This induction occurred without alterations in nuclease sensitivity. Discontinuation of sodium butyrate was followed by a rapid fall in the levels of mRNA. The levels of P-glycoprotein returned to normal with a half-life of about 24 h. In spite of a 20-25-fold increase in the level of mdr-1/Pgp mRNA and P-glycoprotein, the SW-620 cell line did not demonstrate increased resistance to doxorubicin and vinblastine or decreased accumulation of vinblastine. In contrast, in the HCT-15 cell line, a 5-fold increase of mdr-1/Pgp was accompanied by a comparable fall in vinblastine accumulation which was reversed by verapamil. In the SW-620 cell line, the induced protein could be photolabeled using [3H]azidopine. Expression of mdr-1/Pgp appears to correlate with the degree of differentiation. However, its induction is not always accompanied by expression of the multidrug-resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Expression of multidrug resistant gene (mdr-1/P-glycoprotein) in a megakaryoblastic cell line, CMK, and its enhancement during megakaryocytic differentiation.

Multidrug resistance is a severe clinical problem in the chemotherapy of malignant disease. Acute megakaryoblastic leukemia (AMKL) is a rare form of childhood leukemia, and is often resistant to many anti-cancer chemotherapeutic drugs. Here we report the expression of the mdr-1/P-glycoprotein in a cell line, CMK, established from a patient with AMKL. Expression of mdr-1 mRNA in CMK11-5 cells, a well differentiated subline, was higher than in CMK6 cells, a poorly differentiated subline. The level of P-glycoprotein was also higher in CMK11-5 cells. The cytokines interferon-gamma (IFN-gamma), GM-CSF and IL-3, which were shown to induce megakaryocytic differentiation of CMK cells, enhanced the expression of the mdr-1 mRNA and levels of P-glycoprotein. These results imply that differentiated megakaryocytic cells may have higher levels of the P-glycoprotein expression, suggesting a possible normal physiological function of P-glycoprotein in mature megakaryocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Low doses of gamma-rays can induce the expression of mdr gene.

We reported earlier that human cervical carcinoma HeLa cells exposed to 30 fractions of 0.5 Gy gamma-rays became resistant to cisplatin, methotrexate and vincristine, but retained the same sensitivity to gamma-rays and ultraviolet light. The aim of this study was to examine whether a small number of gamma-ray fractions, with a lower daily dose, may also change the sensitivity of preirradiated cells to different cytotoxic drugs. Using the modified MTT staining procedure, we found that cells preirradiated with 5 or 10 daily fractions of only 0.17 Gy gamma-rays did not alter their sensitivity to mitomycin, cisplatin, methotrexate, 5-fluorouracil, etoposide and doxorubicin. However, 10 fractions of gamma-rays induced resistance to vincristine and vinblastine. Our immunocytochemical experiments using monoclonal antibody JSB-1 show that the plasma membrane P-glycoprotein is involved in the induced resistance to Vinca alkaloids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Expression of the multiple drug resistance gene (mdr-1) and epitope masking in chronic lymphatic leukaemia.

Resistance to cytotoxic agents is a common clinical problem in the treatment of chronic lymphatic leukaemia (CLL). The multidrug resistant (MDR) phenotype characterized by increased levels of a specific cell membrane p-glycoprotein, confers cross resistance to a wide range of structurally dissimilar antineoplastic drugs. We have studied the expression of this p-glycoprotein in chronic lymphatic leukaemia measured by immunofluorescence using a monoclonal antibody MRK 16 by flow cytometry. Initial results showed that only 12% of lymphocyte samples from CLL patients showed increased p-glycoprotein, conflicting with a previous observation that 53% of CLL patients had an increased level of mdr-1 mRNA. Treatment of the cells with neuraminidase to remove sialic acid residues increased the proportion of patients showing increased p-glycoprotein to 52%. This suggest that in a subset of CLL patients post translational modification of the protein occurs masking the epitope recognized by MRK 16. Abnormal sialylation patterns associated with malignancy are a well-recognized phenomenon.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Expression of the multidrug-resistance (MDR) gene in breast cancer.

Of the approximately 18,000 new cases of cancer in Venezuela each year, only half can be treated with surgery and radiation. The remainder must be treated systematically using chemotherapy or biological response modifiers. It has become evident that any drug resistant human tumors express the MDR1 gene, since MDR1 RNA levels are elevated in many cancers that do not respond to chemotherapy. Human mammary carcinomas have multiple oncogene alterations, the most frequently reported being overexpression of the oncogenes c-myc, int-2, neu and c-myb. Thirteen specimens of mammary cancer were obtained by biopsy of untreated patients in stage IIIB. All these patients received three cycles of FAC or CMF-L+GM-CSF after biopsy. In the slot blot analysis of RNA from invasive carcinomas, MDR1 and c-myc transcripts were detectable at a high level in 30% of tumors. Two patients with increased levels of MDR1 before chemotherapy did not respond to the treatment and distant metastasis and death occurred in these patients. Another patient, MDR1-negative before therapy, did not respond to CMF-1 + GM-CSF and showed high levels of MDR1 transcripts in a second biopsy which was obtained during surgery.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Multidrug resistance (MDR) gene expression in acute non lymphoblastic leukemia: sequential analysis.

Sequential evaluation of P-glycoprotein expression was performed in 29 patients with acute nonlymphoblastic leukemia using immunocytochemistry with the C219 antibody. At diagnosis, 32% of the patients exhibited more than 5% of the P-gp(+) leukemic cells. Under chemotherapy, 62% of the patients eventually expressed a subset of P-gp positive leukemic cells. After conventional doses of cytosine-arabinoside (Ara-C) and daunorubicin or mitoxantrone, positive P-gp cells were noted in 65% of the cases. This percentage was significantly higher (p = 0.002) than the proportion of positive cases (15%) observed after regimens containing either intermediate doses of Ara-C or cyclosporine A, a P-gp modulator.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

[Relationship between p 53 gene mutation and MDR 1 gene expression in surgically resected non-small cell lung cancer].

The resistance of tumor cells to chemotherapeutic drugs is a major obstacle to successful cancer chemotherapy. Expression of the MDR 1 gene, which encodes for a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of anticancer drugs. Recently, one mutant p 53 form was shown to stimulate the MDR 1 gene promoter in vitro, whereas wild-type p 53 repressed this activity. We examined the relationship between p 53 gene mutation and MDR 1 gene expression in specimens from non-small cell lung cancer patients. Tumor samples were obtained from 21 patients during surgery. Mutations of exon 5 through exon 8 of the p 53 gene were detected by the polymerase chain reaction single strand conformation polymorphism method. MDR 1 expression was semi-quantified by the reverse transcriptase polymerase chain reaction method. We identified p 53 gene mutation in samples from 7 patients. MDR 1 gene expression was observed in samples from 20 patients. The expressivity of the MDR 1 gene tended to be higher in patients with adenocarcinoma. No significant relationship between p 53 mutation and MDR 1 expressivity was observed in our study.

Adenocarcinoma↗