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PubMed2003

[Multidrug resistance and its relationship with neuroendocrine differentiation in non-small cell lung carcinoma].

OBJECTIVE: To study the multidrug resistance (MDR) of non-small lung cancer (NSCLC) and its relationship with neuroendocrine (NE) differentiation. METHODS: NSCLC samples from 113 untreated patients were analyzed immunohistochemically with antibodies to glutathion-s-transferase-pi (GST-pi), multidrug resistance associated protein (MRP), lung resistance associated protein (LRP), neuro-specific enolase (NSE), synaptophysin (SYN) and chromogranin (CgA). RESULTS: (1) The expression of the three proteins was significantly associated with the type of lung carcinoma (P < 0.05), but not with the differentiation and lymph node metastasis. The expression of GST-pi was significantly related with MRP, MRP and LRP (P < 0.05). (2) The positive rates of the NE markers were: NSE, 53.1%; SYN, 26.6%; CgA, 6.2%; and 21.2% for at least two markers. The expression of at least 2 markers was associated with the degree of differentiation (P < 0.05), but not with the type of lung cancer and lymph node metastasis. (3) The expression of the three multidrug resistance related proteins in the positive group for at least 2 markers was significantly lower than that in the negative group (P < 0.05). CONCLUSIONS: The over-expressions of GST-pi, MRP and LRP are important causes of primary multidrug resistance in NSCLC. The differentiation of NE may be one of the factors involved in multidrug resistance.

Adenocarcinoma↗
PubMed2003

Gene expression profiling of malignant mesothelioma.

PURPOSE: Malignant mesothelioma is a uniformly fatal cancer of the pleural and peritoneal spaces. Several challenging clinical problems include poor understanding of the pathophysiology, inaccurate diagnosis from tissue samples, and unsuccessful treatment strategies. The purpose of this study was to use microarray analysis to identify specific gene expression changes in mesothelioma compared with normal mesothelium. EXPERIMENTAL DESIGN: We performed gene expression analysis on mesothelioma tissue specimens from 16 patients and compared these to 4 control pleural tissue samples using cDNA microarray filters with 4132 clones. Multiple normalization and analysis approaches were used. Quantitative reverse transcription-PCR and immunohistochemistry were used to validate results. RESULTS: Genes (166) were significantly up-regulated, and 26 were down-regulated. Validation of 18 genes using real-time PCR confirmed array predictions in every case. Analysis revealed activation of several key pathways including genes involved in glucose metabolism, mRNA translation, and cytoskeletal remodeling. Expression profiling identified processes likely responsible for 18-fluoro-2-deoxy-glucose uptake and tumor localization by positron emission tomography, and a role for hypoxia-inducible factor-1 was suggested. Potentially important up-regulated genes included gp96, lung resistance-related protein, galectin-3 binding protein, the M(r) 67,000 laminin receptor (on tumor vessels), and voltage-dependent anion channels. Prospective testing using reverse transcription-PCR confirmed up-regulation of these novel markers. CONCLUSIONS: Expression profiling revealed marked up-regulation of energy, protein translation, and cytoskeletal remodeling pathways in mesothelioma. Additional genes that could be important in our understanding of the pathogenesis of mesothelioma, aiding in diagnosis, or improving targets for therapy were also identified.

Aged↗
PubMed2003

[Sodium butyrate-induced expression of lung resistance-related gene in human myeloid leukemia K562 cells].

BACKGROUND & OBJECTIVE: Overexpression of lung resistance-related protein(LRP) is involved in multidrug resistance and poor outcome in acute leukemia. This study was designed to investigate the effect of sodium butyrate (NaB) on LRP expression level and the function of LRP in K562 cells. METHODS: Human myeloid leukemia K562 cells, used as an in vitro model, were treated with NaB. The LRP mRNA expression and protein levels in the cells before and after NaB treatment were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry indirect immunofluorescence method,respectively. Intracellular Adriamycin(ADM) location and intracellular daunorubicin(DNR) accumulation were detected by fluorescence microscope and flow cytometry, respectively. RESULTS: Compared with untreated K562 cells, the LRP mRNA level in the cells treated with 2 mmol/L NaB was increased obviously; the protein expression were turned from negative result to positive result and the ratios of positive cells were increased from 1.68% to 35.81%. Intracellular DNR accumulation was decreased in the treated K562 cells and the mean fluorescence of DNR reduced 68.64% compared with the untreated K562 cells. There was strong ADM fluorescence in the nuclei of untreated K562 cells; while the treated K562 cells showed significantly less ADM fluorescence in their nuclei but more fluorescence in the cytoplasm. CONCLUSION: Both the mRNA level and the protein expression of LRP in K562 cells can be increased by NaB induction. LRP induced by NaB is involved in the decreasing anti-cancer drug accumulation and transporting the drugs from the nucleus to the cytoplasm in K562 cells.

Butyrates↗
PubMed2003

Multidrug resistance in hematological malignancy.

The recent treatment of hematological malignancies appears to be unsatisfactory in child and adult patients with acute myeloid leukemia and adult patients with acute lymphocytic leukemia. A major problem in the treatment of leukemia is caused by the development of drug resistance to chemotherapeutic agents, which is already present at diagnosis or after chemotherapy as a minimal residual disease, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemia clone. It was suggested that the mechanisms of drug resistance consist of drug resistance proteins, which work as a drug efflux pump. These are the permeability-related glycoprotein (P-Gp), the multidrug-resistance associated protein (MRP), the lung resistance protein (LRP), and other MDR proteins such as the transporter associated with antigen processing (TAP), anthracyclin resistance associated protein (ARA), MRP 2-7, and breast cancer resistance protein (BCRP). In addition, anti-apoptosis mechanisms, alterations of tumor suppressor genes, altered immunogenicity, drug resistance mechanisms for individual drugs, and clinical risk factors such as white blood cell count, age, and other factors have been reported to act in drug resistance singly or in combinations. Here we describe the update of research on the biology of MDR in the hematological malignancies and also discuss how to overcome MDR and adapt the updated treatment methods in the clinical medical field.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

[Expression of lung resistance protein and multidrug resistance protein genes in bone marrow cells of acute leukemia patients and its clinical significance].

To study the expression of lung resistance protein (LRP) and multidrug resistance protein (MRP) genes in bone marrow cells in patients with acute leukemia and its clinical significance, expression of LRP and MRP mRNA in bone marrow cells from 47 cases of acute leukemia, including 10 refractory or relapsed cases, and 7 normal individuals were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The result s showed that expression of LRP gene was negative in normal individuals. LRP mRNA level in newly treated cases of acute myelocytic leukemia and refractory or relapsed cases was significantly higher than that in normal individuals, increased LRP mRNA level has correlation with lower sensitivity to initial chemotherapy and was associated with reduced overall survival rate. Complete remission (CR) rate in LRP positive patients was lower than that in negative cases. The level of LRP expression was correlated with that of MRP mRNA. In conclusion, the expression of LRP mRNA can predict the treatment outcome and prognosis for acute myelocytic leukemia, prognosis was even worse in LRP and MRP linked expression cases, therefore, LRP was an important resistant factor, determination of LRP and MRP expression can help us to evaluate the prognosis and choose chemotherapy program.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

[Multidrug resistance mediated by membrane P-glycoprotein in acute myeloid leukemia].

A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanisms, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, of more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with the outcome in AML.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

Expression of LRP--lung resistance-related protein in the normal colorectal mucosa and in colorectal carcinoma.

Expression of LRP--lung resistance-related protein was analyzed by immunohistochemical staining with monoclonal antibody LRP-56 in 30 specimens (10 from normal colorectal tissue and 20 from colorectal carcinoma). All normal tissue samples were LRP positive. Strong LRP staining was seen in the surface epithelium and upper parts of the crypts. Similarly, colorectal carcinomas demonstrated strong staining for LRP/MVP. Staining pattern of cytoplasm of carcinoma cells was the same as in the normal mucosa. The overexpression of LRP in the colorectal carcinoma may play a role in the process of carcinogenesis or be a marker of an aggressive phenotype. It seems, the high value of LRP is a predictor of response to chemotherapy and prognoses in various tumor types. (Fig. 7, Ref: 18.).

Carcinoma↗
PubMed2003

[Expression of P-glycoprotein and lung resistance protein in breast carcinoma and its relationship with prognosis].

BACKGROUND & OBJECTIVE: The multidrug resistance of tumor cells is the reason to failure of chemotherapy. The overexpression of P-glycoprotein (P-gp) and lung resistance protein (LRP) play important roles in the multidrug resistance of breast carcinoma. The objective of this study was to investigate the expression of P-gp and LRP in breast carcinoma and its relationship with prognosis. METHODS: Immunohistochemical assay with the LSAB immunostaining technique was used to determine protein expression of P-gp and LRP in the specimens of paraffin-embedded tissues from 151 cases of breast carcinoma and 40 normal breast tissues (control). The results were evaluated on the basis of clinical pathological factors and the survival time of these cases. RESULTS: The expression of P-gp were found in 62 (40.8%) of the breast carcinoma samples and in 1 (2.5%) of control samples. The difference between the two groups was statistically significant (Chi(2)=21.27,P< 0.01). The expression of LRP were found in 121 (80.1%) of the breast carcinoma samples and in 22 (55.0%) of control samples. The difference between the two groups was statistically significant (Chi(2)=10.62,P< 0.01). The expression of P-gp were irrelative to age,tumor size,histotype,lymph nodes metastasis,tissue grading,clinical staging, ER condition,and prognosis. The expression of LRP were found in 62 (88.6%) of 70 cases with positive lymph nodes and 59 (72.8%) of 81 cases with negative lymph nodes. The difference between the two groups was statistically significant (Chi(2)=4.891, P< 0.05). The expression of P-gp were found in 55 (45.5%) of breast carcinomas with positive immunohistochemical reaction of LRP protein; while the expression of P-gp were found in 7(23.3%) of breast carcinomas with negative immunohistochemical reaction of LRP protein. The difference between the two groups was statistically significant (Chi(2)=3.990,P< 0.05). The expression of LRP were positively correlated with the lymph nodes metastases (r=0.197, P< 0.05) and the expression of P-gp (r=0.179,P< 0.05) and irrelative to age tumor size, histotype, lymph nodes metastases, tissue grading,clinical staging, and ER condition. Univariate analysis demonstrated worse disease-free survival in the patients with positive LRP than in those with negative LRP (Chi(2)=6.892,P< 0.01). Multivariate analysis of clinical and pathological data by Cox regression method did not demonstrated that both expression of P-gp and LRP were independent factors affecting the survival of breast carcinoma patients. CONCLUSION: The expression of P-gp and LRP have their characteristics and dissimilarity clinical significance in breast carcinoma tissues. The expression of LRP may correlate not only with MDR but also the lymph nodes metastases,prognosis and expression of P-gp in breast carcinoma tissues.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

[Effect and mechanism of arsenic trioxide on chemosensitivity of human lung adenocarcinoma cells].

OBJECTIVE: To study the apoptosis and chemosensitive effect of As(2)O(3) on human lung adenocarcinoma cell line A549. METHODS: MTT colorimetric assay, immunohistochemical method, flow cytometry and RT-PCR were applied to observe the different effects induced by As(2)O(3) with different concentrations on A549 cells. RESULTS: 1, 2 micro mol/L As(2)O(3) increased Fas expression and inhibited the expression of bcl-2, MRP and LRP; G(1) arrest was observed and the cells were more sensitive to cisplatin. A549 cells in the presence of 5 micro mol/L As(2)O(3) showed growth inhibition and up-regulation of bcl-2, MRP and LRP expressions; but their chemosensitivity to cisplatin did not change. CONCLUSION: As(2)O(3) in low concentrations can increase the chemosensitivity of A549 cells by regulating the expression of apoptosis genes, anti-apoptosis genes and drug-resistant genes and affecting the cell cycle progress.

Adenocarcinoma↗
PubMed2004

P-glycoprotein and multidrug resistance associated protein-1 activity in 132 acute myeloid leukemias according to FAB subtypes and cytogenetics risk groups.

BACKGROUND AND OBJECTIVES: We studied the function of both Pgp and MRP1 to identify subgroups of patients who could benefit from Pgp reversion, and to clarify in different FAB subtypes and in cytogenetic risk groups their expression and function. DESIGN AND METHODS: We examined 132 adults with de novo acute myeloid leukemia (AML) for Pgp and MRP1 expression and function. We correlated our finding with the FAB subtypes and the cytogenetics, and clinical data of our patients. RESULTS: Among FAB subtypes and cytogenetic subgroups, patients with good risk cytogenetics have a low expression and activity of Pgp and MRP1 except patients with inv(16) who have a higher activity of MRP1 than t(8;21) and t(15;17) (p=0.05). All other AML patients, except M5, have a high expression and activity of Pgp. In contrast, M5 have a high expression, but a low activity of Pgp. In this subgroup, M5 with MLL gene rearrangement did not express an active Pgp. Others patients with M5 AML did not have a functional Pgp. Monosomy 7, 11q2.3 gene rearrangement and complex cytogenetic have a higher activity of MRP1 than other cytogenetic (p=0.03). INTERPRETATION AND CONCLUSIONS: Resistance mechanism in M5 was not mediated by Pgp. In contrast, MRP1 may play a role in patients who have a 11q2.3 gene rearrangement, or in M4E with inv(16). Thus trials that modulate Pgp are likely to achieve limited success in AML with low activity of Pgp, i.e., M5 and, AML with good risk cytogenetics.

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

Heterogeneity in the expression of markers for drug resistance in brain tumors.

Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.

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

Multidrug resistance proteins in primary and metastatic soft-tissue sarcomas: down-regulation of P-glycoprotein during metastatic progression.

BACKGROUND: Chemotherapy sensitivity of soft-tissue sarcomas (STS) is limited, which may be due to multidrug resistance (MDR). MDR is associated with expression of P-glycoprotein (P-gp), Multidrug Resistance-associated Protein 1 (MRP1) and Lung Resistance-related Protein (LRP). It is unknown whether in STS metastasis is more resistant than the primary counterpart. MATERIALS AND METHODS: In 35 chemonaive STS and their metastases (86% chemonaive), MDR proteins were immunohistochemically assessed. Eleven metastases presented synchronously, 24 metachronously. Expression was scored positive (>5% positive tumour cells) or negative. RESULTS: P-gp was positive in 31/34 primaries (91%), versus 22/32 metastases (69%) (p=0.005). This difference was significant for metachronous metastases (p=0.008). MRP1 was positive in 18/32 primaries (56%) and 22/33 metastases (67%). MRP1 was more expressed in synchronous metastases than primaries (p=0.047), but for the overall group this significance disappeared. LRP expression did not differ: 27/34 primaries (80%), versus 28/34 metastases (82%). CONCLUSION: P-gp, MRP1, LRP expression in the primary tumours was high. Metastatic progression did not coincide with MDR-protein up-regulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

[Expression and implication of Pgp, MRP, LRP, GST-pi, Topo II alpha in tongue squamous cell carcinoma].

OBJECTIVE: To explore the correlation of chemotherapy efficacy in tongue squamous cell carcinoma(SCC) with expression level of P-glycoprotein(Pgp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathiones-tranferase (GST-pi), DNA topo-isomerase II alpha (Topo II alpha). METHODS: The expression patterns of Pgp, MRP, LRP, GST-pi and Topo II alpha in 40 patients (pre and post-chemotherapy, respectively) with tongue SCC were examined by immunohistochemically labelled streptavidin bioein method (LsAB). RESULTS: The expression ratios of Pgp, MRP, LRP, GST-pi and Topo II alpha in pre-chemotherapy cases were 47.5%, 50%, 35%, 45%, 82.5%, respectively. No relations between expression of Pgp, MRP, LRP, GST-pi, Topo II alpha and clinic indexes were established (P > 0.05). Expression ratios of Pgp, MRP in post-chemotherapy cases were higher than that in pre-chemotherapy cases (P < 0.05). Expression of Pgp and MRP showed relevance with drug resistance (P < 0.05). The co-expression was common, the ratios of co-expression of Pgp, MRP, GST-pi and MRP, GST-pi in chemotherapy non-responders were 40% and 50%, respectively, but 0 in responders. CONCLUSION: The intrinsic multidrug resistance of tongue SCC is relevant to the effects of Pgp, MRP, GST-pi.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

[Establishment of human multidrug-resistant hepatocellular carcinoma cell line (HepG2/Adm) and biological characteristics evaluation].

BACKGROUND & OBJECTIVE: Multidrug resistance (MDR) is considered to be the major obstacle for chemotherapy. In order to reverse tumor MDR in vitro, we designed this study to establish human multidrug-resistant hepatocellular carcinoma cell line (HepG2/Adm) and to investigate its biological characteristics. METHODS: An adriamycin-resistant human hepatocellular carcinoma cell subline (HepG2/Adm) was established in vitro using gradually increased concentration of adriamycin (ADM) in culture. Cell growth was measured and multidrug resistance to multianticancer agents was evaluated by MTT assay. Flow cytometry (FCM) was performed to determine cell cycle,and to assess the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP),lung-related protein (LRP),and glutathione S-transferase (GST), respectively. MDR mRNA expression related to these proteins were determined with reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared to HepG2, HepG2/Adm had a prolonged doubling time of 30.1 hours. The number of cells in S-phase was significantly decreased (5.6+/-0.03)% in HepG2/Adm while those in G1 and G2-phase increased [(4.2+/-0.09)% and (1.5+/-0.08)%, respectively]. Furthermore, HepG2/Adm was resistant to many anti-tumor agents, and its IC(50) of ADM was 26 times higher than that of parent cell line HepG2. Significant overexpression of P-gp, MRP, and GST were detected. RT-PCR showed that mRNA expression of P-gp, MRP, LRP, and GST were significantly increased in HepG2/Adm. CONCLUSION: HepG2/Adm is human multidrug-resistant, and its resistance may be closely related to the overexpression of P-gp, MRP, and GST.

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

Expression and prognostic value of the lung resistance-related protein (LRP) in germ cell testicular tumors.

BACKGROUND: Lung resistance-related protein (LRP) was first detected in a non-P-glycoprotein-mediated multidrug-resistant lung cancer cell line and has been shown to be the major human vault protein. The aim of this study was to evaluate the expression of LRP in germ cell testicular tumors (GCT) and to determine the correlation between LRP expression and the clinical outcome of these tumors. PATIENTS AND METHODS: Seventy cases of primary testicular tumors were investigated. LRP protein was detected by immunohistochemistry and Western blotting methods. LRP mRNA was determined with RT-PCR. Patients' clinical parameters and tumor response to treatment were recorded. RESULTS: With immunohistochemistry, LRP was detected in 29 (41%) out of 70 primary testicular tumors. Twenty-two (63%) out of 35 tumors expressed LRP mRNA and LRP protein on examination by RT-PCR and Western blotting, respectively. Pure teratomas showed significantly higher LRP expression compared to other types of GCTs (p=0.0418). No relationship was demonstrated between the LRP immunostaining and stage of disease (p=0.2263). A significantly higher proportion of patients with LRP-negative tumors achieved complete response than those with LRP-positive tumors (p=0.0155). Patients whose tumors showed expression of LRP had significantly shorter overall survival (p=0.0428) than LRP-negative patients. CONCLUSION: Immunohistochemistry is a reliable method to evaluate LRP expression in testicular germ cell tumors. A positive correlation was found between LRP immunostaining and pure teratomas. LRP expression was associated with an adverse clinical outcome and shorter overall survival. Our findings suggest that LRP has prognostic value in testicular germ cell tumors and can predict clinical outcome.

Adolescent↗
PubMedDate not supplied

Fluorescence-based assessment of LRP activity: a comparative study.

BACKGROUND: Broad resistance to anticancer drugs is a major cause of failure in cancer treatment. The Lung Resistance-related Protein (LRP) is a protein associated with drug resistance, which is involved in nucleo-cytoplasmic transport and is known to predict a poor response to chemotherapy in acute myeloid leukaemia. The only method allowing the detection of LRP activity is based on radio-labelled daunorubicin incorporation. Our goal was to develop a fluorescence-based assay to analyse LRP function. MATERIALS AND METHODS: We used human colon carcinoma cell lines treated with sodium butyrate (NaB) in order to induce LRP expression. Daunorubicin efflux in isolated nuclei was measured by flow cytometry, the localization and quantification of Daunorubicin analysed by confocal laser scanning microscopy (CLSM) and the diffusion coefficient of this drug estimated by Fluorescence Correlation Spectrometry (FCS). RESULTS: According to the method using [14C] Doxorubicin cells incubated with NaB displayed an efflux of Daunorubicin out of isolated nuclei demonstrated by flow cytometry or CLSM. The FCS method was able to evaluate kinetics of Daunorubicin molecules in nucleus and cytoplasm and showed a higher dispersion of Daunorubicin kinetics with cells previously NaB-treated. This argument is in favour of an increase of nucleo-cytoplasmic exchange. CONCLUSION: Using CLSM we showed that LRP was able to modify anticancer drug repartition in the cells. LRP activity assessment needs either isolated nuclei if flow cytometry is employed, or FCS, and only a few cells may be analysed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗