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PubMed2001

[Clinic Significance of Expression of bcl-2 and bax Gene in Patients with Acute Leukemia and its Relationship with mdr-1 Gene Expression]

It is generally accepted that the inhibition of apoptosis is one of the mechanism of drug resistance to tumor. Members of the bcl-2 gene family are the most important regulators in apoptosis. The purpose of this study is to evaluate the value of expression of bcl-2 and bax gene in predicting the prognosis of acute leukemia patients, and to explore the relationship between bcl-2 and bax expression and drug resistance. Seventy patients with acute leukemia entered this study. Expressions of bcl-2, bax and mdr-1 gene were measured by RT-PCR method and FCM. The result showed that: bcl-2 had been widely detected in specimens of blood or bone marrow from acute leukemia patients, the expression levels were much higher than those in normal control (1.46 vs 0.71, P < 0.05), bax expression levels and bax/bcl-2 ratio in patients had no significant difference with the control. No relationships were found between the expression levels of bcl-2 and bax and AL patients' age, sex, platelet counts, hemoglobin levels, percentage of marrow blasts, FAB classification, and S + G(2)M%. Both Bcl-2 protein expression (34.6% vs 69.2%, P < 0.03) and bax/bcl-2 mRNA ratio (37.1% vs 82.9%, P < 0.01) were associated with response to therapy and CR rate, bax/bcl-2 ratio also influences the overall survival time. There was no relationship between bcl-2 and bax expression levels and mdr-1 expression levels.

Journal Article↗
PubMed2006

[Reversal of multidrug resistance in drug-resistant human breast cancer cell line MCF-7/ADR by calmodulin antagonist O-(4-ethoxyl-butyl)-berbamine].

OBJECTIVE: To investigate the reversal effect of O-(4-ethoxyl-butyl)-berbamine (EBB) on multidrug resistance (MDR) in MCF-7/ADR cell. METHODS: 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the antitumor effect of EBB and determine the reversal effects of different concentrations ( < or = IC20) of EBB on MCF-7/ADR cell. Flow cytometry was applied to observe the intracellular accumulation of Rh123 and cell cycle in the presence of EBB. The expressions of MDR-related genes mdr 1 and topoisomerase II b (top II b) were evaluated by reverse transcription-polymerase chain reaction. RESULTS: The sensitivity of MCF-7/ADR to adriamycin (ADR) was enhanced up to 50. 40, 89.80, and 14.88 folds after exposure of the cells to 3 micromol/L EBB, 7.5 micromol/L EBB, and 10 micromol/L verapamil (VPL), respectively. After 2 hours of incubation with 6 micromol/L EBB, intracellular Rh123 accumulation in MCF-7/ADR cells was increased to the level comparable to that in MCF-7 cells. When 6 micromol/L EBB was added together with 2 micromol/L ADR, MCF-7/ ADR cells showed to be arrested in the G2/M phase. The declination of mdr 1 gene expression was observed when 6 micromol/L EBB, 12 micromol/L EBB, and 10 micromol/L VPL were added for 48 hours; meanwhile, the expression of top II b mRNA showed no significant change. CONCLUSION: EBB has a strong reversal effect on MDR in MCF-7/ ADR cell, which may be achieved by enhancing the arrestment of MCF-7/ADR cells at G2/M phase and increasing intracellular drug concentration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

[Reversal of multidrug resistance of leukemia cell line in vitro by antisense phosphorothioate oligonucleotide].

OBJECTIVE: To investigate the effectiveness of 14 mer antisense phosphorothioate oligonucleotide (AS-SODN) complementary to the published multidrug resistance gene (mdr(1) gene) sequence to reverse multidrug resistance of leukemia cell line. METHODS: 50% inhibitory concentration (IC(50)) of K562 cell line resistant to adriamycin (K562/ADM cell line) was determined by the tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the concentration of daunorubicin (DNR) in the cell by flow cytometry, the level of P170 by immunohistochemical staining technique and the level of mdr(1)-mRNA by half-quantitative RT-PCR (the ratio of mdr(1)/beta(2)-MG). RESULTS: Treatment of K562/ADM cell line with 2 micromol/L AS-SODN reduced the level of both the mdr(1)-mRNA and P170. The ratio of mdr(1)/beta(2)-MG reduced from (2.07 +/- 0.16) to (1.57 +/- 0.14), and positive rate of P170 expression decreased from (98.26 +/- 1.35)% to (18.30 +/- 6.50)%. Accordingly, the concentration of DNR in cell increased. With these findings, IC(50) to ADM reduced from 25.72 mg/L to 6.97 mg/L and relative efficiency of modulation was 73.01%. CONCLUSION: Antisense oligonucleotide targeting mdr(1) gene can reduce md(1)-mRNA, block P170 expression so as to increase the sensitivity of K562/ADM cell line to chemotherapy drugs.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1994

Volume-sensitive chloride currents in four epithelial cell lines are not directly correlated to the expression of the MDR-1 gene.

It has been shown recently that heterologous expression of human MDR-1 gene, which is responsible for multidrug resistance during cancer therapy, causes appearance of volume-sensitive Cl- currents, thus suggesting that the product of the MDR-1 gene (the P-glycoprotein) has a Cl- channel activity (Valverde, M. A., Diaz, M., Sepulveda, M. A., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992) Nature 355, 830-833). In the present work, we have tested four epithelial cell lines both for the expression of MDR-1 gene and for the presence of volume-sensitive Cl- currents. LoVo/H and LoVo/Dx cells derive from a human colon adenocarcinoma, the latter cell line being resistant to high concentrations of the antitumoral drug doxorubicin. 9HTEo- cells were obtained by transformation of human tracheal epithelium. The 9HTEo-/Dx cell line was established from these cells by selection in doxorubicin. As expected, higher levels of P-glycoprotein expression were detected in LoVo/Dx and 9HTEo-/Dx by means of reverse transcriptase polymerase chain reaction technique, indirect immunofluorescence, and Western immunoblot assays. In contrast with these data, the size of swelling-induced Cl- current was the same in the sensitive cell line and in its drug-resistant counterpart. Actually, the Cl- conductance of 9HTEo- and 9HTEo-/Dx was 4-fold higher than that of either LoVo/H or LoVo/Dx cells. This indicates that the amplitude of this conductance is not directly related to the expression of the MDR-1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Congenital expression of mdr-1 gene in tissues of carcinoma and its relation with pathomorphology and prognosis.

AIM:To detect the congenital expression patterns of mdr-1 gene in commonly encountered malignant tumors in clinic, and the relationship between the expression of mdr-1 gene and the prognostic morphology in esophageal carcinomas.METHODS:A total of 151 resected samples of malignant tumors without preoperative treatment were taken from Anyang City Tumor Hospital.The congenital expression of their mdr-1 gene was detected with reverse transcription polymerase chain reaction (RT-PCR) and was compared with each other.The positive incidence of mdr-1 gene in 46 samples of esophageal carcinoma was compared with their differentiated grades, TNM stages and macroscopic types, and the precautions and advantages of RT-PCR were evaluated.RESULTS:All the 151 samples were confirmed to be malignant histopathologically, including cancers of stomach and gastric cardia (n = 51), esophagus (n = 46), colorectum (n = 16),breast (n = 15), thyroid (n = 10), lung (n = 9) and uterine cervix (n = 24). The positive expression rate of their mdr-1 gene was 33.3%, 37%, 31.3%, 13.2%, 40%, 55%, and 0% respectively. All the 46 samples of esophageal carcinoma were pathologically confirmed to be squamous cell carcinoma. The total expression rate of their mdr-1 gene was 37% (17/46), 35% (6/17), 40% (8/20), and 33% (3/9) for differentiation grade I, II and III respectively. The expression rate of TNM classification was 33% (6/18), 40% (5/12) and 37% (6/16) in stage IIa, IIb andIII. The expression rate was 33% (3/9) in ulcerous type, 37% (3/8) in constrictive types, 33% (5/15) in fungoid types, and 40% (6/14) in medullary types.No statistically significant difference was found.CONCLUSION:Compared with other methods, RT-PCR is more simple, reliable and accurate in detecting mdr-1 gene expression in tissues of tumor. The overexpression of mdr-1 gene in these neoplasms suggested that cases should be handled differently for chemotherapy with rational use of drugs. Excision is the chief treatment for carcinoma of esophagus. The expression of mdr-1 gene in tissues of esophageal cancer is correlated with the parameters of tumor molecular biology which are independent of histopathological morphology.

Journal Article↗
PubMed1997

[The relationship between in vitro chemosensitivity of human breast cancer to MDR related drugs and expression of mdr-1 gene].

OBJECTIVE: To study the relationship between in vitro chemosensitivity of human breast cancer to MDR related drugs and expression of mdr-1 gene. METHODS: We measured the chemosensitivity of 56 human breast cancers to MDR related drugs by MTT assay in vitro and level of mdr-1 mRNA in these samples by RT-PCR technique. RESULTS: The expression of mdr-1 gene in the breast cancer resistant to drugs in vitro was increased significantly. The level of mdr-1 mRNA was not correlated with Imax%, but correlated with IC50 statistically. CONCLUSION: These results support that the increased expression of mdr-1 gene is a major cause of resistance to MDR related drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

[Expression of mdr-1 gene in cancer tissue and its association with morphological indexes of esophageal carcinoma].

OBJECTIVE: To detect the levels of mdr-1 gene expression in fresh untreated esophageal carcinomas, and to correlate these levels to current prognostic indicators of morphology. METHODS: mdr-1 gene expression of 46 untreated esophageal carcinoma was investigated with reverse transcription polymerase chain reaction (RT-PCR), and compared with the positive incidences among differentiated grades, TNM stages and macroscopic types of cancer. RESULTS: All 46 samples were pathologically squamous cell carcinoma. The positive incidence of mdr-1 gene expression was 37% (17/46) in the whole group, and 35% (6/17), 40% (8/20), 33% (3/9) for differentiated grade I, II and III respectively. The expression rate of 33% (6/18), 40% (5/12), and 37% (6/16) was for TNM stage IIa, IIb, and III respectively. Macroscopically, the positive incidence was 37% (3/8) in constrictive, 33% (5/15) in fungating, 40% (6/14) in medullary, and 33% (3/9) in ulcerative type. There were no significant differences in each category system of morphology. CONCLUSION: Because of highly expressive level of mdr-1 gene in untreated esophageal carcinoma, we should choose appropriate chemotherapeutic regimen for esophageal Ca. The expression of mdr-1 gene in untreated esophageal cancer was independent of morphologic prognostic indexes without correlation between mdr-1 gene expression and morphological indexes.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1993

Amplification and overexpression of the mouse mdr 1a gene in nine independently derived multidrug-resistant SEWA murine cell lines.

Many different drugs may be used in selecting cells for multidrug resistance (MDR). Enhanced expression and/or gene amplification is known to cause overproduction of membrane-bound 170,000 P-glycoproteins, responsible for the MDR. In rodents, the P-glycoproteins are encoded by a small gene family: mdr 1a, mdr 1b, and mdr 2. To evaluate the relationship between the pattern of MDR and the selecting drug, nine MDR sublines were independently selected from a sensitive mouse tumor cell line, SEWATC13K, using three different drugs. Each MDR subline displayed amplification of one or more of the three mdr genes, but only one, mdr 1a, was consistently overexpressed. Thus, our results indicate that the pattern of mdr gene amplification and overexpression is independent of the selective agent. Furthermore, in four of the MDR sublines, where all three mdr genes had been originally amplified, pulsed field gel electrophoresis (PFGE) revealed that amplification of mdr 1a, only, was a second step of gene amplification. In addition, the gene for the calcium-binding protein, sorcin, was coamplified in eight of the nine MDR sublines. The sorcin gene was overexpressed in seven of these eight sublines. Finally, hybridizations with a probe homologous with a putative region of RFLP (restriction fragment length polymorphism), indicated that the amplified sequences originate from one or the other of the two homologous chromosomes with no preference.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Quantification of MDR-1 gene expression in canine tissues by real-time reverse transcription quantitative polymerase chain reaction.

MDR-1 gene product mediated multidrug resistance is thought to play a major role in the outcome of chemotherapy in some canine tumors, especially malignant lymphoma. In the present study, MDR-1 RNA expression in normal lymph node and liver tissue as well as in tumor biopsies from 23 dogs with lymphomas and two dogs with liver tumors was measured by real-time RT-quantitative PCR. MDR-1 gene expression was detected in all samples analyzed. Comparably high MDR-1 RNA levels were measured in all normal liver tissues, one of the lymphomas and a cholangiocarcinoma. MDR-1 expression levels in canine lymphomas were found to vary over a wide range with most tumors expressing relative low levels. Interestingly, gastrointestinal lymphomas expressed higher MDR-1 RNA levels than multicentric lymphomas (p = 0.03). In conclusion, real-time RT-quantitative PCR appears to be a suitable method for sensitive and quantitative determination of MDR-1 gene expression in canine normal and neoplastic tissues.

Animals↗
PubMed1996

Correlation between expression of mdr-1 gene and oncogenes in human promyelocytic leukemic HL60 cell line and sublines.

AIM: To study the relationship between expression of oncogenes and multiple drug resistant (MDR) phenotype. METHODS: The drug resistant level of HL60 cell line and its sublines were determined with flow cytometry. RNA Dot blot hybridization was used to identify the expression of oncogenes and mdr-1 gene. RESULTS: The expression of mdr-1 gene was in the opposite relation with c-myc expression, but in the positive relation with c-H-ras gene expression in the multiple drug resistant cell lines. In non-MDR cell line HL60/RA, the expression levels of mdr-1, c-myc, and c-H-ras were the same as HL60 parental cells. CONCLUSION: Multiple drug resistance is related to not only mdr-1 expression, but also some oncogenes expression level.

Drug Resistance, Multiple↗
PubMed1997

[Inherent mdr-1 gene expression in fresh tumor tissue specimens from several high-incidence malignancies].

OBJECTIVE: To ascertain frequency of inherent mdr-1 gene expression in several common neoplasms. METHODS: One hundred fifty one surgically resected tumor specimens confirmed pathologically to be malignant from preoperatively untreated cancer patients were studied. Expression of mdr-1 gene was examined by RT-PCR. RESULTS: The frequency of primary mdr-1 gene expression was 33.3% for cancer of the stomach and gastric cardia (17/51), 37% for cancer of the esophagus (17/46), 31.3% for cancer of the colon and rectum (5/16), 13.2% for cancer of the breast (2/15), 40.0% for cancer of the thyroid (4/10), 55.0% for cancer of the lung (5/9) and 0% for cancer of the uterine cervix (0/4). CONCLUSION: Primary mdr-1 gene expression is relatively of frequent occurrence as detected by RT-PCR technique.

Adenocarcinoma↗
PubMed1996

Expression of MDR-1 gene in transitional cell carcinoma and its correlation with chemotherapy response.

PURPOSE: Expression of the mdr-1 gene has been correlated with the chemoresistance mechanisms of some cancer models. In the present study, we tried to evaluate mdr-1 gene expression in transitional cell carcinoma (TCC) in both cultured cells and clinical tumors. The expression status of mdr-1 was further correlated with the response to chemotherapy in both systemic and intravesical models. MATERIALS AND METHODS: We evaluated mdr-1 expression levels by reverse transcription polymerase chain reaction and Southern blotting (RT-PCR-SB) and the activity of P-glycoprotein (P-gp) by flow cytometric rhodamine-123 retention and efflux study in 10 TCC cell lines, 2 doxorubicin-resistant sublines (RLs), T24/A and NTUB1/A, and 2 cisplatin-RLs, T24/P and NTUB1/P. Eighty-eight clinical tumors with their benign counterparts were also assayed by RT-PCR-SB to determine mdr-1 expression status. Of the 88 TCC cases, 28 were treated with systemic and 60 with intravesical chemotherapy. Response to chemotherapy in either form was correlated with mdr-1 expression status. RESULTS: By RT-PCR-SB, mdr-1 expression signals were observed in only 2 of the 10 TCC cell lines; only 1 of these had a strong signal and active P-gp function. The other, bearing a weak signal, was negative for active P-gp function. All of the 4 RLs studied showed elevated mdr-1 transcript levels as compared with their mdr-1 negative parental cell lines. Doxorubicin-RLs showed much stronger expression signals than cisplatin-RLs. Active P-gp functions were observed in the 2 doxorubicin-RLs but not in the 2 cisplatin-RLs. The efflux of rhodamine-123 in cells with active P-gp function can be significantly inhibited by 10 microM. verapamil. Of the 88 clinical tumors, 62 (70.5%) were positive and 26 (29.5%) were negative for mdr-1 expression by RT-PCR-SB. All benign counterparts of the 88 tumors were positive for mdr-1 expression. However, no differences in chemotherapy responses were found between the positive and negative mdr-1 expression groups in either systemic chemotherapy (p = 0.32, one-tailed Fisher's exact test) or intravesical chemotherapy (p = 0.52, Cox-Mantel log rank test). CONCLUSIONS: Expression of mdr-1 was not commonly seen in TCC cell lines but can be significantly induced by chronic exposure to doxorubicin. Benign transitional cell epithelia seemed to universally express the mdr-1 gene. However, clinical TCCs lost mdr-1 transcript expressions in about 30% of cases. Most important, it appeared that mdr-1 expression status did not correlate with the response to chemotherapy in either systemic or intravesical models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements.

P-glycoprotein (P-gp) and the drug metabolizing enzymes have major pharmacokinetic effects. Variability in tacrolimus absorption is influenced by P-gp activity which, in turn, is affected by single nucleotide polymorphisms (SNPs) within the multidrug resistance-1 gene (MDR-1). Tacrolimus dose requirements of 206 stable renal transplant patients were related to MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes: C-G-C and T-T-T. Lower dose-normalized blood tacrolimus concentrations were achieved for: 2677-GG genotype patients, as compared to 2677-TT, and for 3435-CC patients as compared to 3435-TT patients. There was a small, but significant, difference in dose requirements between haplotypes C-G-C and T-T-T patients, which was not significant when patients were subclassified as producers and non-producers of cytochrome P450 3A5 (CYP3A5). The activities of CYP3A5 and P-gp have been shown to influence bioavailability of several drugs. Our data suggest that MDR-1 haplotypes have a relatively minor association with tacrolimus pharmacokinetics.

Adolescent↗
PubMed1989

Conformational effects of amino acid substitutions in the P-glycoprotein of the mdr 1 gene.

The P-glycoprotein of the mdr 1 gene is responsible for the phenomenon of multidrug resistance in human cells. The presumed drug-binding site of the wild-type P-glycoprotein contains a glycine at position 185. A mutant P-glycoprotein which contains valine at this position causes cells to retain resistance to colchicine, but to lose cross-resistance to other drugs such as the chemotherapeutic agents vinblastine and Adriamycin. This has been hypothesized to be due to a conformational change in the protein induced by the amino acid substitution. Using conformational energy analysis, we have determined the allowed three-dimensional structures for the wild-type and mutant proteins in the region of position 185. The results indicate that the wild-type protein adopts a unique left-handed conformation at position 185 which is energically unfavorable for the protein with L-amino acids (including valine) at this position. This conformational change induced by amino acid substitutions for Gly 185 could explain the differences in binding to the P-glycoprotein of various drugs and, hence, the differences in drug resistance exhibited by various cell lines expressing these proteins.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Multidrug resistance in Leishmania donovani is conferred by amplification of a gene homologous to the mammalian mdr1 gene.

Drug resistance is a major impediment to the effective treatment of parasitic diseases. The role of multidrug resistance (mdr) genes and their products in this drug resistance phenomenon, however, remains controversial. In order to determine whether mdr gene amplification and overexpression can be connected to a multidrug resistance phenotype in parasitic protozoa, a mutant strain of Leishmania donovani was generated by virtue of its ability to proliferate in medium containing increasing concentrations of vinblastine. The vinblastine-resistant strain, VINB1000, displayed a cross-resistance to puromycin and the anthracyclines, a growth phenotype that could be attributed to an impaired ability to accumulate the toxic drugs. By using the polymerase chain reaction, two different DNA fragments, LEMDR06 and LEMDRF2, were amplified from leishmanial genomic DNA, and each amplified fragment encoded a product that was significantly homologous to parts of the mammalian P-glycoprotein. In the VINB1000 strain, the mdr gene recognized by the LEMDR06 probe was amplified approximately 50-fold in copy number, whereas the mdr genes that hybridized to LEMDRF2 or to a fragment of the previously characterized ltpgpA gene were not amplified. Moreover, the VINB1000 cell line expressed a LEMDR06 gene transcript of 12.5 kb in size that was not detected in the parental wild-type strain. To furnish a functional test for mdr gene amplification and expression in L. donovani, the L. donovani gene recognized by the LEMDR06 polymerase chain reaction product, ldmdr1, was isolated from a genomic library, transfected into wild-type cells, and amplified over 500-fold by selection in 0.5 mg of G418 per ml. The resulting transfectants were resistant to all drugs to which VINB1000 cells were resistant and sensitive to all drugs to which VINB1000 cells were sensitive. These studies demonstrate that amplification of the ldmdr1 gene either by direct selection or subsequent to transfection can confer a drug-resistant phenotype in parasitic protozoa similar to that observed for MDR mammalian cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

MDR-1 gene expression is a minor factor in determining the multidrug resistance phenotype of MCF7/ADR and KB-V1 cells.

The relevance of MDR-1 gene expression to the multidrug resistance phenotype was investigated. Drug-resistant cells, KB-V1 and MCF7/ADR, constantly expressed mRNA of the MDR-1 gene and were more resistant to vinblastine and adriamycin than drug-sensitive cells, KB-3-1 and MCF7. The drug efflux rate of KB-V1 was the same as KB-3-1 although the MDR-1 gene was expressed in only the resistant cell. The higher intracellular drug concentration of KB-3-1 than KB-V1 was due to the large drug influx. In the case of MCF7 and MCF7/ADR, the influx and efflux of the drug had nearly the same pattern and drug efflux was not affected by verapamil. The amount of ATP, cofactor of drug pumping activity of P-glycoprotein, was not changed by the resistance. These observations suggested that drug efflux mediated by MDR-1 gene expression was not a major determining factor of drug resistance in the present cell systems, and that the drug resistance could be derived from the change in drug uptake and other mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

[Expression and clinical significance of mdr-1 gene in lymphoma].

BACKGROUND & OBJECTIVE: It is still unclear whether overexpression of mdr-1 gene play a role in the chemotherapy resistance of lymphoma. This study was designed to investigate P-glycoprotein(P-gp) and mdr-1 mRNA levels of lymphoma and to observed the impact of P-gp level upon chemotherapy response. METHODS: Ten samples of relapsed lymphoma and 21 samples of untreated lymphoma were assessed by flow cytometry(FCM). The mdr-1 mRNA levels were determined by real-time reverse-transcription PCR assay simultaneously in eighteen samples. The impact of P-gp levels upon chemotherapy response was observed in seventeen patients. RESULTS: Nineteen Percent (4/21) patients overexpressed P-gp at diagnosis as compared to 60%(6/10) in relapse(P = 0.012). The copy numbers of mdr-1 mRNA were 4 x 10(2)-1.32 x 10(4) copies/microgram RNA in untreated group and 4 x 10(2)-4 x 10(4) copies/microgram RNA in recurrent group. There existed significant difference in the distribution of mdr-1 mRNA expression between these two groups, P < 0.05. The complete response rates were 46% (6/13) in P-gp non-overexpression group and 25% (1/4) in P-gp overexpression group(P = 0.60). CONCLUSION: Relapsed lymphomas highly express P-gp and mdr-1 mRNA. The overexpression of mdr-1 gene may play a role in the multidrug resistance of relapsed lymphoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias.

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗