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PubMed2001

Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection.

BACKGROUND: Multidrug resistance gene (MDR-1) overexpression has been correlated with tumor aggressiveness and worse prognosis in some human neoplasms. The aim of this study is to evaluate the clinical value of MDR-1 mRNA expression as a prognostic factor after surgical resection in human hepatocellular carcinoma (HCC). METHODS: MDR-1 mRNA levels in tissue samples from 34 patients with HCC, who underwent surgical resection, were measured by quantitative northern blot analysis. We stratified these patients into two groups according to a ratio of MDR-1 mRNA levels of HCC to nontumorous tissue; MDR-1 mRNA ratio > or = 1.0 and < 1.0. The overall and disease-free survival rates were analyzed using multivariate regression analysis. RESULTS: The median survival periods were 10.3 and 35.8 months for patients with the MDR-1 mRNA ratio > or = 1.0 and < 1.0, respectively, and the corresponding 5-year survival rates were 33 and 54%, respectively, P < 0.05. The multivariate analysis revealed that TNM stage and MDR-1 mRNA ratio were independent factors for predicting overall survival after surgical resection. CONCLUSION: This study suggested that the measurement of the MDR-1 mRNA levels in HCC and nontumorous liver tissue might be a useful prognostic factor after surgical resection in patients with HCC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Functional complementation of yeast ste6 by a mammalian multidrug resistance mdr gene.

Multidrug resistance in mammalian tumor cells is associated with the overexpression of mdr genes encoding P-glycoproteins, which function as drug efflux pumps. A yeast homolog of mdr, STE6, mediates export of a-factor mating peptide. Yeast MATa cells carrying a ste6 deletion produce no extracellular a-factor and therefore are defective in mating. Expression of a complementary DNA for the mouse mdr3 gene in a yeast ste6 deletion strain restored ability to export a-factor and to mate. A mutation (a serine to phenylalanine substitution at amino acid 939) known to affect the activity of the mdr3 gene product abolished its ability to complement the yeast ste6 deletion. Thus, functions of P-glycoproteins in normal mammalian cells may include the transmembrane export of endogenous peptides.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

[Clinical significance of MDR gene expression in malignant pleural effusion and ascites and solid tumors].

OBJECTIVE: To discuss the guiding significance of multidrug resistance (MDR) gene expression for monitoring the clinical effectiveness of chemotherapy upon cancer, and to analyze the MDR1 and glutnthione-s-transferase(GST-pi) mRNA expression rates in primary breast cancer, and their correlation with the clinical outcome and prognosis. METHODS: The mRNA expression levels of MDR1 in 16 cases with malignant pleural effusion and ascites and 102 cases of solid tumors were measured using semiquantitative RT-PCR assay. The MDR1 and GST-pi mRNA expression rates in 84 cases of breast cancer, out of the 102 cases of solid tumors, were also studied in the same way. RESULTS: (1) An average coincidence rate of 84.5% was found between the mRNA expression level of MDR1 and the clinical response to chemotherapy in the 16 cases with malignant pleural effusion and ascites and 18 cases of solid tumors. (2) The positive rate of MDR1 mRNA expression in primary breast cancer tissue was 79.7%, with the medium and high levels as high as 33.3%, while the positive rate of GST-pi mRNA expression was 33.3%, with the medium and high expression levels being as low as 4.8%. There was a highly significant difference between the two groups (P < 0.01). The positive rates of MDR1 mRNA in the group having received chemotherapy before surgery and the group not receiving chemotherapy before surgery were 87.8% and 68.6% respectively, showing a lymph nodes and in the group without metastases in axillary lymph nodes were 89.1% and 68.4% respectively, indicating a significant difference (P < 0.05). The positive rates of GST-pi mRNA in the group suffering distant metastases and the group not suffering distant metastases were 71.4% and 20.6% respectively, showing a significant difference (P < 0.05). The GST-pi mRNA expression rates in the estrogen receptor (ER)- and progesterone receptor (PR)-positive groups were higher than those in the ER- and PR-negative groups, indicating a significant difference (P < 0.05) . CONCLUSION: The mRNA expression level of MDR1 has a relatively high correlation with the clinical response to chemotherapy, and thus can be used to monitor the effectiveness of chemotherapy. MDR1 is the main drug resistance mechanism in breast cancer. Chemotherapy before surgery induces MDR1 mRNA expression. MDR1 e xpression and GST-pi mRNA expression serve as a significant prognostic indicator for breast cancer, thus having guiding significance for assessing prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

[The MDR gene and cellular sensitivity to various effects].

mdr-Transfected K-562 cells revealed a relatively high resistance to cytotoxic monokines and ionizing radiation as compared to parental cells. Taken together with what is known about the resistance of mdr-expressing cells to multiple cytotoxic drugs, our results point to malignant cells having universal mechanisms of chemo-, bio- and radioresistance.

Cell Division↗

PubMed1991

Co-amplification and over-expression of two mdr genes in a multidrug-resistant human colon carcinoma cell line.

The human P-glycoprotein gene family contains the mdr1 and the mdr3 gene. The mdr1 P-glycoprotein is over-expressed in multidrug resistant (MDR) tumor cells and is believed to play a role in the elimination of certain cytotoxic drugs used in the chemotherapy of cancer. The mdr3 gene has not been found to be amplified or over-expressed in MDR cells. In this study, gene-specific mdr gene probes were developed for the detection of the gene and the total mRNA level. Southern and Northern hybridization analyses showed that the mdr genes and the mRNA levels were increased 30--40-fold in a MDR human colon cancer cell line. In addition, this MDR cell line had an altered growth rate and morphology and detectable double minute chromosomes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer.

BACKGROUND: Proliferating cell nuclear antigen (PCNA), a proliferation marker, epidermal growth factor receptor (EGFR), a glycoprotein that plays a role in tumorigenesis by binding the mitogenic epidermal growth factor, and P-glycoprotein, the mdr gene product, are considered to be of prognostic relevance in different tumor types. Parameters that allow prediction of the course of disease in colorectal cancer would aid the development of improved treatment strategies. METHODS: Immunohistochemical staining was performed on paraffin-embedded sections of 82 colorectal adenocarcinomas and 18 lymph node metastases. EGFR and P glycoprotein expression was evaluated semiquantitatively; PCNA expression was analyzed quantitatively. RESULTS: An inverse relationship between the percentage of PCNA-positive cells and survival times could be demonstrated, survival differed significantly among the quartiles (P < 0.02). The median and range of the percentage of PCNA-positive cells in primary tumors and lymph node metastases were similar. The extent of EGFR expression also revealed significant differences concerning survival times; patients with more than 50% stained tumor cells had a poorer prognosis than those with less than 50% stained cells. P-glycoprotein expression was found to have no influence on survival. CONCLUSIONS: Knowledge of the percentage of PCNA-positive cells could be especially helpful in deciding whether to treat patients with localized disease further because adjuvant chemotherapy affects mainly dividing cells and should, therefore, be more successful in tumors with high proliferative activity.

Adult↗

PubMed1994

[Effects of moxibustion on the function of MDR gene product, P-glycoprotein (P-170)].

The experiments were performed on BABL/c mice with S-180R adriamycin resistant tumor cells. This animal model was used to analyze the drug accumulation in the S-180R cells by flow cytometer. The drug accumulation presents the pump activity of multidrug resistance (MDR) gene product P-glycoprotein (P-170) in the cell membrane, A weak inhibition was found when moxibustion at Guan-Yan point alone. And a very significant inhibition was observed in the presence of low-dosage of verapamil, but not at high dose. This study may develop a new way to research the mechanism of acupuncture and moxibustion at molecular level, and may be useful to overcome the anticancer drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Multiple drug resistance, the MDR gene, and the law of maximum perversity as it applies to oncology: an hypothesis.

The so-called Law of Maximum Perversity, generally stated, says that when more than one outcome is possible, that which is the more adverse is the outcome most likely to occur. In medical oncology, the most obvious expression of this law is the fact that all the neoplasms that are most sensitive to cytotoxic drugs and are most curable by chemotherapy, are rare and in numerical terms are not important as causes of cancer-related deaths. Conversely, the most commonly encountered neoplasms that make up the bulk of oncologic practice and that cause over 90 per cent of cancer-related deaths, are all relatively resistant to cytotoxic agents and are virtually never curable by chemotherapy administered in standard (i.e. non-transplant) doses. It is postulated that the biological properties and the normal tissue distribution of the multidrug resistance (MDR) gene and its product p-170 glycoprotein explain the observed incidences and distribution of tumours that are sensitive or insensitive to cytotoxic agents. The normal role of MDR is to protect cells from environmental carcinogens, and the tissues that are most at risk, and most richly supplied with MDR, will produce drug-resistant neoplasms. Current attempts at MDR reversal may facilitate the treatment of some tumours that are resistant to multiple drugs but may cause severe toxic effects as a consequence of abrogating the largely unknown physiologic functions of P-170.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Postnatal development of organic cation transport and mdr gene expression in mouse kidney.

The apical surface of the proximal tubular epithelium is the site of both P-glycoprotein localization and postulated active secretion of organic cations in the mammalian kidney. P-glycoprotein has been shown to act as a pleiotropic drug efflux pump across the cell membrane of tumor cells expressing the multidrug resistance phenotype, whereas the renal organic anion and organic cation secretory systems serve the function of pleiotropic drug transport across the proximal tubule epithelium. Because most known substrates for P-glycoprotein are organic cations, we tested the hypothesis that the physiological function of this protein in the kidney is to mediate renal organic cation secretion. In one approach, we compared the postnatal development of organic cation transport with that of kidney mdr gene expression. Cimetidine-sensitive uptake of classical substrates for renal secretion (N-methyl nicotinamide and tetraethylammonium) into kidney slices developed gradually in neonate mice, reaching adult capacity in 4 to 6 weeks. P-glycoprotein and its mRNA, as estimated by immunohistochemical methods and RNAse protection analysis, were undetectable at birth and were expressed abruptly at the adult level between 2 and 3 weeks of age. In another approach, classical inhibitors of renal organic cation secretion (cimetidine and cyanine 863) failed to reverse resistance to adriamycin in Chinese hamster ovary and P388 cell lines, which possess the phenotypic traits of multidrug resistance. These results suggest that the cimetidine-sensitive component of organic cation secretion is mediated by a protein other than the P-glycoprotein in the mammalian kidney.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1990

Differential transport properties of two mdr gene products are distinguished by progesterone.

P-glycoprotein is an integral membrane protein that is overproduced in multidrug-resistant cells. It is likely to function as an energy-dependent drug efflux pump to maintain intracellular drug concentrations below cytotoxic levels. Individually isolated multidrug-resistant murine cell lines, J7.V1-1 and J7.V3-1, overproduce P-glycoproteins encoded by the mdr1b and mdr1a genes, respectively. The transport properties of these cell lines and the drug binding characteristics of their P-glycoproteins have been compared. It is concluded that 1) the mdr1a gene product is a more efficient efflux pump than the mdr1b gene product, and 2) whereas a single class of vinblastine binding sites is present in J7.V1-1 membrane vesicles, there appears to be two classes of such sites in J7.V3-1 membrane vesicles. The effects of verapamil and progesterone, two compounds that are known to interact with P-glycoprotein, have been analyzed in the two cell lines. Progesterone inhibited drug binding and efflux and increased drug sensitivity to vinblastine with more potency in J7.V1-1 cells than in J7.V3-1 cells. It is concluded that progesterone, but not verapamil, can be used to differentiate the two mdr gene products in the mouse.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1990

Increased mdr gene expression and decreased drug accumulation in a human colonic cancer cell line resistant to hydrophobic drug.

An adriamycin-resistant human colonic cancer cell line was characterized. This clone exhibits the classical multidrug resistance (MDR) phenotype, being cross-resistant to hydrophobic drugs such as colchicine, and vinblastine. In contrast, this clone shows a normal response to DNA-damaging agents. The appearance of MDR in these cells was linked to a decreased accumulation of the drug [3H]colchicine as compared to the drug-sensitive cells. This MDR line expressed 80-100 fold increased levels of the specific 4.5-kb mdr mRNA, and a gene amplification. Our results indicate that MDR in human colonic cancer cells can result from increased expression of at least one member of the mdr gene family.

Antineoplastic Agents↗

PubMed1989

Mechanisms of multidrug resistance in HL60 cells. Analysis of resistance associated membrane proteins and levels of mdr gene expression.

HL60 cells isolated for resistance to Adriamycin do not contain P-glycoprotein, as determined with immunological probes. These cells, however, are multidrug resistant and defective in the cellular accumulation of drug. In view of these findings, we have examined in greater detail certain properties of the HL60/Adr cells and have compared these properties to an HL60 drug-resistant isolate (HL60/Vinc) which contains high levels of P-glycoprotein. The results of these studies demonstrated that verapamil induces a major increase in cellular drug accumulation in both HL60/Adr and HL60/Vinc isolates. An 125I-labeled photoaffinity analog of verapamil labeled P-glycoprotein contained in membranes of HL60/Vinc cells. In contrast, this agent did not label any protein selectively associated with drug resistance in membranes of the HL60/Adr isolate. The photoactive dihydropyridine calcium channel blocker [3H]azidopine and [125I]NASV, a photoaffinity analog of vinblastine, labelled P-glycoprotein in membranes from HL60/Vinc cells, whereas in experiments with the HL60/Adr isolate there was no detectable labeling of a drug resistance associated membrane protein. Additional studies have been carried out to analyze membrane proteins of HL60/Adr cells labeled with the photoaffinity agent 8-azido-alpha-[32P]ATP (AzATP32). The results demonstrate that this agent labeled a resistance associated membrane protein of 190 kilodaltons (P190). P190 is essentially absent in membranes of drug-sensitive cells. Labeling of P190 with AzATP32 in membranes of resistant cells was blocked completely when incubations were carried out in the presence of excess unlabeled ATP. Additional studies were carried out to analyze mdr gene amplification and expression in sensitive and resistant cells. Experiments carried out with human 5',mdr1 (1.1 kb) and mdr3 (1.0 kb) cDNAs demonstrate that both of these sequences were highly amplified in the HL60/Vinc isolate. Only the mrd1 gene sequence however, was overexpressed. In contrast, there was no detectable amplification or overexpression of mdr1 or mdr3 sequences in HL60/Adr cells. The results of this study thus identify a new nucleotide binding protein which is overexpressed in membranes of HL60 cells isolated for resistance to Adriamycin. P190, which exhibits properties distinct from P-glycoprotein, possibly functions in the energy-dependent drug efflux system contained in the HL60/Adr resistant isolate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

Increased mdr gene expression and decreased drug accumulation in multidrug-resistant human melanoma cells.

Multidrug-resistant clones of a drug-sensitive human malignant melanoma cell line were isolated by single-step selection in culture medium containing either vincristine (4.5 ng/ml or 7.5 ng/ml), vinblastine (3 ng/ml), or colchicine (8 ng/ml). This protocol yielded primary colonies showing relatively low (4- to 24-fold) levels of drug resistance. These clones exhibit the classical multidrug resistance (MDR) phenotype, being cross-resistant to Vinca alkaloids, anthracyclines, colchicine, and actinomycin D. The appearance of an MDR phenotype in these cells was linked to a decreased accumulation and increased efflux of the drug [3H]vinblastine when compared to the drug-sensitive melanoma cell line. This increased drug efflux was dependent on the presence of cellular ATP and could be reduced by treatment of the cells with rotenone and deoxyglucose. A partial human mdr complementary DNA clone was used to monitor the degree of amplification and the level of transcription of this gene in the cloned lines. All 5 MDR sublines expressed increased levels of the specific 4.5-kilobase mdr mRNA, but did not show mdr gene amplification. Our results indicate that relatively low levels of drug resistance, similar to those observed clinically and in experimental xenografts, can be achieved by single-step drug selection and result from increased expression of at least one member of the mdr gene family.

Base Sequence↗

PubMed1995

Expression of multidrug resistance (mdr) gene(s) in primary lymphoid organs of chicken immune system during embryonic development.

The presence of a multidrug resistance (MDR) related protein, P-170, in normal and pathological lymphoid cells has been described. The present report evaluates the expression of the mdr 1 gene by using the reverse Polymerase Chain Reaction (PCR) on cells obtained from the thymus and bursa of chicken embryos starting from day 12 until hatching. Results show that the thymic cells are positive from day 12 to the end of the observation period. In contrast, mdr mRNA was detected in the bursa from day 14 to day 17 of embryonic life. Possible relationships between the expression of mdr and the development of T and B lymphocytes are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis.

A variant, MS23, of murine thymoma W7 cells, previously selected for its resistance to low concentrations of dexamethasone, is cross-resistant to unrelated drugs such as puromycin and colchicine. We report here that transcription of the mouse mdr1 gene is activated and P-glycoprotein is expressed in MS23 cells. Moreover, additional variants with increased resistance to dexamethasone and other drugs can be isolated from MS23 by stepwise selections in dexamethasone and colchicine. In one such variant (S7CD-5), the mdr1 gene is amplified and the mdr protein overexpressed. These variants have classical mdr characteristics: they accumulate reduced concentrations of drugs (including dexamethasone), and both drug sensitivity and intracellular accumulation can be restored by verapamil. The variants are most resistant to glucocorticoids with both 11- and 17-hydroxyl groups. The results indicate that we have identified a new form of glucocorticoid resistance, one associated with expression of the mouse mdr1 P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression.

UNLABELLED: Early diagnosis of multidrug-resistance (MDR) development is extremely important for the judicious choice of treatment protocols in breast cancer chemotherapy. In this study, the mechanism of 99mTc-sestamibi uptake by nine human breast tumor cell lines was analyzed as a function of P-glycoprotein (PgP) expression. METHODS: Technetium-99m-sestamibi radioactivity incorporation into the cells was determined after different times of incubation at 37 degrees C. We analyzed the mechanism of 99mTc-sestamibi uptake as follows: (a) effect of temperature (4 degrees C); (b) influence of extracellular 99mTc-sestamibi concentration; and (c) competitive inhibition of cell uptake with cold 99mTc-sestamibi. Technetium-99m-sestamibi uptake was compared to the level of PgP determined by Western blotting. The PgP reversing effect of verapamil was evaluated at different drug concentrations (50, 200, 500 microM). RESULTS: Technetium-99m-sestamibi uptake plateaued at 60 min, which was 14 times lower at 4 degrees C than at 37 degrees C and was directly proportional to the extracellular concentration between 0.3 and 10 nM. Technetium-99m-sestamibi percentage uptake by cells expressing nonimmunodetectable levels of PgP was significantly higher (7.3% +/- 0.6% (s.d.) to 14.9% +/- 1.9%) than that by cells expressing high PgP levels (0.7% +/- 0.4%, p < 0.001). In the presence of verapamil, a known reverser of PgP functions, 99mTc-sestamibi uptake was increased by a factor of 2 in cells expressing no detectable levels of PgP and by a factor of 12 in cells with high PgP levels. CONCLUSION: Technetium-99m-sestamibi uptake by these breast tumor cells is energy-dependent but not specific. These data suggest that 99mTc-sestamibi imaging may be used as a noninvasive technique to diagnose the presence of MDR in breast tumors in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

[The clinical significance of MDR-1 gene expression in the hemopoietic cells of patients with acute leukemias in different phases of the disease].

AIM: Analysis of cytostatic therapy effects on expression of gene MDR-1 in hemopoietic cells of patients with acute leukemia (AL) in complete clinicohematological remission (CCHR). MATERIALS AND METHODS: The study included 48 AL patients. 27 of them were untreated, 25 were resistant to or had recurrent AL. 4 patients were followed up. Bone marrow mononuclear fraction was investigated. Expression of MDR-1 gene in the cells was evaluated at hybridization. RESULTS: High expression of MDR-1 gene occurred in leukemic blast cells either upon achievement of CCHR or at least 6 months after its onset. When using schemes of chemotherapy containing two potential inductors of gene MDR-1, expression of this gene was registered significantly more frequently than in using schemes based on one inducing drug (p < 0.05). Frequency of occurrence of enhanced expression of gene MDR-1 in leukemic blasts significantly correlated with frequency of CCHR (p < 0.05). Correlation between occurrence of the gene's expression in normal hemopoietic cells in CCHR and occurrence of early AL recurrences was not found. CONCLUSION: The findings may facilitate design of new AL treatment programs.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Intracellular concentration of protease inhibitors in HIV-1-infected patients: correlation with MDR-1 gene expression and low dose of ritonavir.

BACKGROUND: Protease inhibitors (PIs) are substrates for the P-glycoprotein (P-gp/170) encoded by the multi-drug resistance gene (MDR-1). HIV infection is associated with increased expression of P-gp. The role of MDR gene overexpression in clinical pharmacokinetics is not known. METHOD: We determined by HPLC, at trough and peak levels, the current PI concentrations in plasma (P) and in peripheral blood mononuclear cells (PBMCs) (intracellular concentration [IC]) from 49 HIV-infected patients receiving different treatment combinations: nelfinavir ([NFV] n = 12); indinavir ([IDV] n = 10); amprenavir ([APV] n = 5); ritonavir (RTV) 100 bid/IDV 800 mg bid (n = 6); RTV 400 bid/IDV 400 mg bid (n = 3); RTV 100 bid/saquinavir (SQV) 600 mg tid (n = 9); APV 600 bid/RTV 100 mg bid (n = 4). We determined the mean ratio of intracellular/plasma PI concentration for each treatment group. The MDR-1 gene expression was determined by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). HIV viral load was simultaneously measured. RESULTS: 49 patients (mean age 41 +/- 8.7 years; mean CD4 cell count 418 [57-972]; mean HIV RNA 2.1 +/- 0.8 log(10)) were included in the study. Patients who overexpressed the MDR-1 gene had significantly lower trough intracellular PI levels (p =.02) or lower intracellular accumulation of PI (p =.042). Patients treated with low-dose RTV in combined regimens with detectable RTV intracellular concentration showed lack of MDR-1 gene expression (p =.01). Patients with HIV RNA < 40 copies/mL had significantly higher RTV intracellular accumulation (p =.029). CONCLUSION: In HIV-infected patients, IC of PI is inversely correlated with MDR-1 gene overexpression. Undetectable viral load was associated with the use of low-dose RTV, probably linked to better intracellular accumulation of the drug. Nevertheless, further investigation is needed to confirm these results.

Adult↗