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Immunohistochemical detection of LRP protein in the normal human lung.

In this study, we have determined the LRP (lung resistance-related protein) by immunohistochemical method. LRP belongs to proteins which cause the multidrug resistance (MDR). It has been found in various normal human tissues, where it plays a protective role against toxic compounds. Multidrug-resistant cells distribute the cytotoxic drug into the perinuclear region and then redistribute it back into the cytoplasm. It is just a hypothesis today that LRP can mediate drug resistance by regulating both the cytoplasmic redistribution and the nucleocytoplasmic transport of drugs. In order to detect LRP we have used the paraffin-embedded sections of the normal human lung tissue. LRP was predominantly located in two regions: 1) in bronchial epithelial cells and 2) in alveolar macrophages. Positive cells were coloured brown and showed strong reactivity. Negative control included the omitting of primary antibody and replacing it by buffer solution. Bronchial epithelial cells and alveolar macrophages stayed uncoloured, i.e. unreactive. (Fig. 5, Ref. 17.).

Bronchi↗

Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers.

This investigation describes the expression and interindividual variability in transcript levels of multiple drug efflux systems in the human jejunum and compares the expression profiles in these cells with that of the commonly used Caco-2 cell drug absorption model. Transcript levels of ten-drug efflux proteins of the ATP-binding cassette (ABC) transporter family [MDR1, MDR3, ABCB5, MRP1-6, and breast cancer resistance protein (BCRP)], lung resistance-related protein (LRP), and CYP3A4 were determined using quantitative polymerase chain reaction in jejunal biopsies from 13 healthy human subjects and in Caco-2 cells. All genes except ABCB5 were expressed, and transcript levels varied between individuals only by a factor of 2 to 3. Surprisingly, BCRP and MRP2 transcripts were more abundant in jejunum than MDR1 transcripts. Jejunal transcript levels of the different ABC transporters spanned a range of three log units with the rank order: BCRP approximately MRP2 > MDR1 approximately MRP3 approximately MRP6 approximately MRP5 approximately MRP1 > MRP4 > MDR3. Furthermore, transcript levels of 9 of 10 ABC transporters correlated well between jejunum and Caco-2 cells (r2 = 0.90). However, BCRP exhibited a 100-fold lower transcript level in Caco-2 cells compared with jejunum. Thus, the expression of a number of efflux protein transcripts in jejunum are equal to, or even higher than, that of MDR1, suggesting that the roles of these proteins (in particular BCRP and MRP2) in intestinal drug efflux have been underestimated. Also, we tentatively conclude that the Caco-2 cell line is a useful model of jejunal drug efflux, if the low expression of BCRP is taken into account.

ATP-Binding Cassette Transporters↗

Expression of multidrug resistance protein and messenger RNA correlate with (99m)Tc-MIBI imaging in patients with lung cancer.

UNLABELLED: In vitro studies have shown that (99m)Tc-sestamibi (MIBI) is a transport substrate for the P-glycoprotein (Pgp) pump and the multidrug resistance-associated protein (MRP) pump. However, whether MRP and lung resistance protein (LRP) affect tumor accumulation and efflux of (99m)Tc-MIBI in lung cancer is not known. In this study, we explored whether Pgp and the other pumps, MRP and LRP, affect tumor accumulation and efflux of (99m)Tc-MIBI in lung cancer. METHODS: Thirty-four lung cancer patients who underwent surgery were examined. Before surgery, (99m)Tc-MIBI SPECT was performed 15 min and 180 min after injection, and early uptake, delayed uptake (L/Nd), and washout rate (L/Nwr) of (99m)Tc-MIBI were obtained. Pgp, MRP, and LRP expression were investigated by immunohistochemistry. The messenger RNA (mRNA) level of Pgp, MRP, and LRP was determined by real-time reverse-transcription polymerase chain reaction. The lung cancer (99m)Tc-MIBI images were correlated with protein and mRNA expression. RESULTS: The mean L/Nd of the Pgp (-) group was significantly higher than that of the Pgp (++) group (P = 0.0324). The Pgp (++) group had a higher L/Nwr than did the Pgp (-) group (P = 0.0269). The mean L/Nd of the Pgp mRNA low-expression group was significantly higher than that of the Pgp mRNA high-expression group (P = 0.0127). The Pgp mRNA high-expression group had a higher L/Nwr than did the Pgp mRNA low-expression group (P = 0.0825). No appreciable correlation was found between the lung cancer (99m)Tc-MIBI images and the expression of MRP or LRP on the level of protein or mRNA. CONCLUSION: These data suggest that an increased level of Pgp expression correlates with a low accumulation on delayed scans and a high L/Nwr of (99m)Tc-MIBI in lung cancer. Neither MRP nor LRP expression on the level of either protein or mRNA correlated significantly with tumor accumulation or efflux of (99m)Tc-MIBI in lung cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[Clinical significance of the expression of lung resistance protein in non-small cell lung carcinomas].

OBJECTIVE: To investigate the expression of the lung resistance-related protein (LRP) in non-small cell lung carcinomas (NSCLC) and evaluate its clinical significance. METHODS: Using immunohistochemistry, LRP was examined in 69 NSCLC specimens obtained by either transbronchial biopsy via fibrobronchoscopy or transcutaneous needle biopsy or surgical resection. Of the 69 patients from whom tumor specimens were obtained, 52 were male and 17 were female. RESULTS: LRP expression was detected in 39/69 (57%) tumor specimens. There was no correlation between LRP expression and NSCLC histological classification (P > 0.05). No significant differences were found in gender and among age groups. The positive rates of LRP were 67% (18/27), 55% (17/31), 52% (23/44), 64% (16/25), 83% (5/6), 57% (36/63) and 50% (3/6) in adenocarcinoma, squamous, staging T1-2, T3-4, N3, M0 and M1 respectively. It was shown that LRP expression was not associated with primary tumor size and metastasis status (N,M). NSCLC patients with positive LRP expression responded more poorly to chemotherapy than those with negative LRP expression (P < 0.05). CONCLUSIONS: The frequencies of multidrug resistance caused by LRP are similar between adenocarcinoma and squamous. Expression of LRP is related to multidrug resistance of NSCLC, which in turn related to the efficacy and prognosis of chemotherapy. The examination of LRP expression may be valuable for choice of chemotherapy regimen.

ATP-Binding Cassette Transporters↗

[Expression of multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) in human rectal carcinomas and its clinical significance].

OBJECTIVE: To investigate the expression and clinical significance of multidrug resistance-associated protein(MRP) and lung resistance protein(LRP) in rectal carcinoma. METHODS: Fiftyseven paraffin embeded primary rectal carcinoma specimens were examined by immunohistochemical staining. RESULTS: Of the 57 tumour specimens examined, 28(49.1%) and 24(42.1%) were positively immunostaned for MRP and LRP, respectively. Co-expression of the two proteins was observed in 10(17.5%) specimens. Positive immunostaning of either of the two proteins was not correlated with cell differentiation and Dukes stage (P > 0.05). Patients with MRP-positive tumours had shorter survival than MRP-negative patients (P < 0.05). No such correlation was found for LRP expression, nor was found between MRP and LRP expression. CONCLUSION: Positive MRP expression in rectal carcinoma appears to be an independant factor of prognostic significance. To examine its expression may help guide rational comprehensive therapy of rectal carcinoma.

Adult↗

[Expression of LRP, MRP and MDR1 in non-small-cell lung cancer and its clinical significance].

OBJECTIVE: To detect expression of lung resistance protein (LRP), multidrug resistance-associated protein(MRP) and multidrug resistance 1(MDR1) mRNA, and its clinical significance in non-small-cell lung cancer (NSCLC). METHODS: RT-PCR was used to investigate mRNA expression of the above mentioned genes. RESULTS: The frequency of expression of LRP, MRP and MDR1 was 74.2%, 80.3% and 37.9%, respectively. A significant positive correlation was observed between LRP and MRP(r = 0.47, P = 0.001), but this association was found neither between LRP and MDR1, nor between MRP and MDR1. The expression of LRP, MRP and MDR1 did not vary with the grade of cell differentiation and TNM staging. In adenocarcinomas which responded to chemotherapy, there was lowered expression of both LRP and MRP than those which did not respond. In chemo-responsive squamous-cell carcinomas, however, this was true of LRP expression only. The median survival time of NSCLC patients with co-expressed 2 and 3 drug resistance related genes was significantly reduced. CONCLUSION: The intrinsic multidrug resistance of NSCLC involves the combined effects of LRP, MRP and MDR1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[Comparison of stepwise and pulse induced cisplatin-resistant ovarian cancer cell sublines].

OBJECTIVE: To investigate the mechanism responsible for acquired cisplatin resistance induced in human ovarian cancer cell lines by different methods. METHODS: Two resistant cell lines, Skov3/CDDP-P and Skov3/CDDP-50, were established by pulse or stepwise exposures of ovarian cancer cell line Skov3 to cisplatin (CDDP) for 10-12 months with the drug sensitivity monitored by MTT test. The growth rate and cell cycle were compared. The intracellular drug concentration was measured by FACS after 1 hour incubation in 20 mumol/L ADM. The drug-resistance-associated genes: MDR1, MRP, LRP and GST-pi were monitored by RT-PCR and western blotting. RESULTS: The resistance indexes (RI) of Skov3/CDDP-P and Skov3/CDDP-50 were 3.7 and 48.6 to cisplatin, 4.0 and 33.0 to Taxol, 2.2 and 7.3 to adriamycin, 1.5 and 3.4 to VP16, and the intracellular ADM concentration was lowered by 34.6% and 47.2% respectively. Both resistant cell lines grew slowly and exhibited changes in morphology and cell cycle. The expression of the resistance-associated genes MDR1, MRP and LRP was enhanced in both resistant cell lines. However, Skov3/CDDP-50 showed greater increase in MDR1 but Skov3/CDDP-P showed more in MRP. There were no significant changes in GST-pi expression either at mRNA or protein level. The TOPO II activity decreased slightly in both resistant cell lines. CONCLUSION: Stepwise induction of cisplatin resistance in ovarian cancer is more readily acquired in which multiple drug-resistance-associated genes are involved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[The clinical significance of lung resistance-related protein gene (lrp), multidrug resistance-associated protein gene (mrp) and mdr-1/p170 expression in acute leukemia].

OBJECTIVE: To evaluate the relationship between lrp, mrp, mdr-1/p170 and multidrug resistance in acute leukemia (AL). METHODS: 85 AL patients were divided into three groups: untreated (A), complete remission (B) and relapsed/refractory (C). The expression of lrp, mrp and mdr-1 mRNA was detected with RT-PCR assay and that of p170 measured with immunocytochemistry. RESULTS: The frequency of lrp gene expression in ANLL A, B and C group was 11.11%, 9.09% and 36.36%, in ALL A, B, C group it was 0%, 20.00% and 46.67%; the frequency of mrp gene expression in ANLL A, B, C group was 44.44%, 9.09% and 59.09%, in ALL A, B, C group it was 28.57%, 20.00% and 53. 33%; the frequency of mdr-1 gene expression in ANLL A, B, C group was 0%, 4.54% and 59.09%, in ALL A, B, C group it was 0%, 0% and 33.33%; p170 expression in ANLL C group was (9.45 +/- 14.66) %, it was the highest value in the three groups; statistics showed that there was no correlationship among the expressions of lrp, mrp and mdr-1 gene, P > 0.05; patients with lrp and mdr-1 expression had a lower complete remission (CR) percentage than those who had not in the untreated group; the combination of lrp, mrp and mdr-1 gene detection turned out to be a more sensitive, specific and accurate way in evaluation of multidrug resistance (MDR). CONCLUSION: Overexpression of one or more genes of lrp, mrp and mdr-1/p170 is associated with MDR in AL. Expression of lrp, mrp and mdr-1/p170 is good indicators in clinical MDR. Two or three factors of lrp, mrp and mdr-1 are more valuable in the evaluation of MDR than any one of these three factors. The mechanisms of mrp, lrp and mdr-1 causing MDR are different, it means that the mechanisms of MDR are complicated the combination of lrp, mrp and mdr-1/p170 detection may be the best way to evaluate MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[The expression of multiple drug resistance associated genes in ovarian cancer].

OBJECTIVE: The aim of the investigation was to find out the relationship between the expression of multidrug resistance gene (MDR1), multidrug resistance protein (MRP), lung resistance protein (LRP) and glutathione S-transferase pi (GST-pi) with the clinical pathological characteristics and the prognosis in the ovarian cancer patients who never received chemotherapy before operation. METHODS: The expression of MDR1, MRP, LRP and GST-pi in 41 cases of ovarian cancer, 25 cases of benign ovarian tumor and 12 normal ovary tissue were investigated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In normal ovary, benign tumor and ovarian cancer, the positive expression of MDR1 was 0.0%, 0.0% and 29.3%, the positive of MRP was 16.7%, 12.0% and 53.7%, the positive of LRP was 25.0%, 52.0% and 87.8%, the positive of GST-pi was 8.3%, 12.0% and 51.2% respectively. The ratios of co-expression of multiple genes in ovarian cancer were much higher than that in benign ovarian tumor. All tested genes showed no significant relationship to the clinical stage, histological type and the differentiation of the tumor except that the expression of MDR1 and MRP was closely related to the differentiation (P < 0.05). The non-responders to platinum or taxol based combination chemotherapy exhibited higher ratios of MDR1 and MRP expression than the responders (P < 0.05). Furthermore, the co-expression phenomenon was more common in non-responders. CONCLUSIONS: Multiple gene expression is involved in drug resistance in ovarian cancer. The co-expression of MDR1, MRP, LRP and GST-pi is higher in ovarian cancer than that in benign ovarian tumor and normal ovary tissue. The expression of MDR1 and MRP is closely related to the tumor differentiation and the response to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[The clinical significance of lung resistance protein (LRP) gene expression in patients with acute leukemia].

OBJECTIVE: To investigate the relationship between the expression of lung resistance protein (LRP) gene and drug resistance in patients with acute leukemias (AL). METHODS: Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)was used to examine the expression of LRP gene in AL patients and 15 normal subjects. Beta(2) microglobulin (beta(2)MG) was used as internal reference. LRP/beta(2)MG ratio >or= 0.3 was defined as LRP positive. RESULTS: The positivity percentage of LRP gene expression in newly diagnosed group was 32.4%. The first complete remission rate was 84.0% and 33.0% in LRP negative and LRP positive patients, respectively. The difference was significant (P < 0.005). The expression level of LRP mRNA and the positivity percentage of LRP in relapsed/refractory group were significantly higher than that in newly diagnosed group (P < 0.01). The expression level of LRP gene in normal subjects and long-term survival groups was very low and correlated with FAB subtypes. The mdr-1 gene was examined simultaneously in 61 AL patients. No significant correlation was found between the expression of LRP and mdr-1 gene (P > 0.5). Coexpression of LRP and mdr-1 genes in the same AL patient might result in the worst prognosis. CONCLUSION: High expression of LRP gene leads to clinical drug resistance and is an unfavorable factor to AL patients of prognosis.

Acute Disease↗

[Mechanisms of drug resistance and reversal of the resistance].

The mechanisms for the resistance to anticancer agents have been vigorously studied and many factors that are involved in the resistance were found. Among the members of ABC transporter superfamily, P-glycoprotein, MRP1-5 and BCRP are involved in the drug resistance. LRP, identified as the major vault protein, is also related to drug resistance.

ATP-Binding Cassette Transporters↗

[The relationship between expression of lung resistance-related protein gene or multidrug resistance-associated protein gene and prognosis in newly diagnosed acute leukemia].

OBJECTIVE: To evaluate the relationship between the expression of lung resistance-related protein (lrp) gene or multidrug resistance-associated protein (mrp) gene and prognosis in untreated acute leukemia (AL) patients. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine the expression of lrp and mrp gene in 58 newly diagnosed AL patients. RESULTS: The positive rate of lrp and mrp gene expression in newly diagnosed acute lymphocytic leukemia (ALL) group was 15.0% and 40.0% and it was 15.8% and 42.1% in newly diagnosed acute nonlymphocytic leukemia (ANLL) group. In both the ALL and ANLL groups, the difference of the first complete remission rate in lrp negative and in lrp positive patients was not significant (P > 0.05), the same results were found with mrp gene. The difference of the first complete remission rate between lrp(+)/mrp(+) and lrp(-)/mrp(-) patients was significant (P < 0.05). There was no relationship between lrp and mrp gene. CONCLUSION: Neither lrp nor mrp gene as a single indicator to forecast original multidrug resistance is sensitive, but lrp combined with mrp as one indicator will be sensitive.

ATP-Binding Cassette Transporters↗

[Preliminary study of sodium butyrate-induced expression of lung resistance-related protein in K562 cells].

OBJECTIVE: To investigate the effect of sodium butyrate (NaB) on the expression level of lung resistance-related protein (LRP) in K562 cells. METHODS: K562 cells, used as an in vitro model system, were treated with NaB to induce differentiation of the cells. LRP mRNA expression and protein levels in the cells were detected by reverse transcriptase-PCR (RT-PCR) and flow cytometry, respectively. RESULTS: A 1-day treatment with 2 mmol/L NaB induced the gene expression of LRP to increase to the maximum in the cells, and a 3-day treatment caused the corresponding protein level to increase to the maximum. CONCLUSION: Both the mRNA level and the protein expression of LRP can be induced by NaB in K562 cells.

Butyrates↗

[Expression of lung resistant-related protein in ovarian cancer and its clinical significance].

BACKGROUND & OBJECTIVE: It was reported that there was negative correlation between the over-expression of lung resistant-related protein (LRP) and the sensitivity of cisplatin and cyclophosphamide. Also it was reported that the over-expression of LRP could predict the chemosensitivity and prognosis of ovarian cancer, and it was an independent index of remission and exist period. This study was designed to investigate the function of LRP in cisplatin resistance and the relationship with prognosis of ovarian cancer by combining with the chemosensitivity test. METHOD: 1. ATP bioluminescence assay was used to determine the drug sensitivity of 50 specimens of fresh epithelial ovarian cancer tissues. Patients' responses were obtained by accepted clinical assessment methods after three treatment courses. 2. Expression of LRP in 50 paraffin specimens of ovarian cancer was determined using immunohistochemistry. RESULTS: 1. The non-overexpression of LRP in ovarian cancer was 24%, and the overexpression of LRP was 76%. 2. The non-overexpression of LRP in the cisplatin-sensitive ovarian cancer was 10/12(75%), while in the cisplatin-resistance was 3/12(25%). There was no significantly different. 3. The over-expression of LRP was increased in advanced and low grade ovarian cancer, and there was significantly different. CONCLUSIONS: Expression of LRP is related to stages, grades, and chemosensitivity of ovarian cancer, and it could become an index of screening drug and judging the prognosis of patients.

Adult↗

Induction of drug resistance and protein kinase C genes in A2780 ovarian cancer cells after incubation with antineoplastic agents at sublethal concentrations.

We examined the inducibility of drug resistance (MDR1, MRP1, LRP) and protein kinase C (PKC) isozyme (alpha, epsilon, eta, theta, tau, zeta) corresponding genes in A2780 ovarian cancer cells after a 24-hour treatment with adriamycin (ADR), camptothecin (CAM), etoposide (ETO) or vincristine (VCR). Sublethal concentrations of drugs were used to exclude short-term effects caused by selection. Cell cycle analysis was performed to identify possible correlation between resistance factors, PKC isozymes and proliferation. We found a mostly combined induction of MDR1, LRP, PKC tau and PKC zeta by CAM, ETO and VCR. PKC alpha, epsilon, eta and theta gene expression altered variably. Cell cycle analysis showed that A2780 cells responded with a marked G2/M arrest after a 24-hour treatment with CAM, ETO and VCR but an association between the induction of PKC isozymes corresponding genes and proliferation was not seen. Our analysis points to a possible link between atypical PKC tau/PKC zeta and MDR1/LRP in cytostatic stress response of cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response.

PURPOSE: The aim of this study was to investigate whether expression of particular drug resistance genes in primary operable breast cancer correlates with response to first-line chemotherapy in advanced disease. EXPERIMENTAL DESIGN: We determined mRNA levels of BCRP, LRP, MRP1, MRP2, and MDR1 in 59 primary breast tumor specimens of patients who received chemotherapy as first-line systemic treatment after diagnosis of advanced disease. The relative expression levels were measured by quantitative real-time reverse transcription-PCR and subsequently analyzed in relation to the type of response to chemotherapy, the length of progression-free survival (PFS), and post-relapse overall survival. RESULTS: For each of these drug resistance genes, a large variation in expression level was observed among the tumors of the different patients. When analyzing mRNA expression in relation to overall response, it was found that the median expression level of these five drug resistance genes in the responding tumors, as compared with nonresponding tumors, was markedly lower. Classification of tumors as high versus low with respect to the expression level of these genes showed that the overall response in the MDR1-high subset (17%), as compared with the MDR1-low subset (68%), was significantly lower (P = 0.005). Although similar differences in response rate were found for subsets of tumors stratified by the expression level of the other drug resistance genes, none of the observed differences were statistically significant. However, in the subgroup of patients treated with anthracycline-based chemotherapy (5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide), a correlation between response and the expression of BCRP and MRP1 (only PFS) was found, whereas such an association was not present in the cyclophosphamide, methotrexate, and 5-fluorouracil-treated group of patients. Furthermore, high expression of LRP as well as MDR1 was found to be significantly associated with a poor PFS (P = 0.04 and P < 0.001, respectively). For lung resistance-related protein, this association was limited to 5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide. Expression levels of BCRP, MRP1, or MRP2 were not related with the length of PFS. Furthermore, no correlation between the expression level of these drug resistance genes and post-relapse overall survival was found. CONCLUSIONS: In this pilot study, MDR1 expression in primary breast tumors was inversely related with the efficacy of first-line chemotherapy, and high expression level was a significant predictor of poor prognosis for patients with advanced disease. Apart from MDR1, the expression levels of BCRP, LRP, and MRP1 might have some additional predictive value for clinical outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[Expression and significance of MRP, GST-pi, Topo IIalpha, and LRP in gastric carcinoma].

BACKGROUND & OBJECTIVE: Multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi(GST-pi), topoisomerase IIalpha(Topo IIalpha)and lung resistance protein (LRP) play important roles in the multidrug resistance(MDR)of tumor chemotherapy. There were few reports on combined determination of the expression of MRP, GST-pi, Topo IIalpha and LRP in gastric carcinoma. This study was designed to investigate the expression and significance of MRP, GST-pi, Topo IIalpha and LRP in gastric carcinomas. METHODS: Immunohistochemistry SP method was used to determine the expression of MRP, GST-pi, Topo IIalpha, and LRP in 90 tumor samples from the patients with gastric carcinoma. Chi-square test and Fisher exact test were used to analyze the significance of the expression. RESULTS: (1)The positive expression rates of MRP, GST-pi, Topo IIalpha and LRP in gastric carcinoma were 88.9%, 91.1%, 74.4%, and 87.7%, respectively. They were all significantly higher than those in normal stomach tissues (P< 0.05). (2)The expression levels of MRP, GST-pi, and LRP in well-moderated differentiation adenocarcinoma were significantly higher than those in poor differentiation adenocarcinoma. The expression of Topo IIin well-moderated differentiation adenocarcinoma was significantly lower than that in poor differentiation adenocarcinoma. There was no difference between the expression levels of them in different degree of invasion or with lymph nodes metastasis and without lymph nodes metastasis (P > 0.05). (3) There was no correlation in any two items among the expression levels of MRP,GST-pi, topo IIalpha,and LRP. CONCLUSION: MRP, GST-pi, topo IIalpha,and LRP play important roles in the primary MDR of gastric carcinoma. The expression of them are associated with the differentiation, but are not associated with the invasion degree and lymph node metastasis.

Adult↗

Evaluation of MDR1, LRP, MRP, and topoisomerase IIalpha gene mRNA transcripts before and after interferon-alpha, and correlation with the mRNA expression level of the telomerase subunits hTERT and TEP1 in five unselected human melanoma cell lines.

Intrinsic and acquired multidrug-resistance (MDR) and the activity of the enzyme telomerase have been demonstrated in human melanoma. A direct regulation of the MDR pathways and of telomerase by interpheron-alpha (IFN-alpha), which is currently used in the therapy of advanced cutaneous melanoma, has also been hypothesized. In this study, we used five melanoma cell lines not selected in vitro for drug resistance (Me665/2/21, Me665/2/60, HT-144, SK-MEL-28, and SK-MEL-5), which in a previous study, had shown different responses to IFN-alpha in terms of proliferation, apoptosis, telomerase activity and expression of mRNA for the human telomerase reverse transcriptase (hTERT). We investigated the expression of the multidrug resistance (MDR1) gene, multidrug resistance protein (MRP), lung resistance protein (LRP), topoisomerase IIalpha (Topo IIalpha), hTERT, and telomerase-associated protein (TEP1), which is shared by telomerase and vault MDR proteins at the mRNA expression level, using the reverse transcription-PCR (RT-PCR). All cell lines showed an intrinsic expression of hTERT, TEP1, and MDR gene transcripts (only MDR1 mRNA was under the detection level in SK-MEL-28 cells). After IFN-alpha exposure, we observed either no effect, a trend towards a decrease of hTERT, MRP, and Topo IIalpha, or an increase of TEP1, MDR1, and LRP mRNA expression in some cell lines. Effects were usually temporary and not always significant. No correlation was found between hTERT and TEP1 mRNA expression, whereas significant positive correlations were found between TEP1 and MDR1 mRNA, and between TEP1 and LRP mRNA. IFN-alpha modulates differently MDR gene transcripts in human melanoma cell lines. Positive correlation between TEP1 and LRP also seems to identify them as common targets of IFN-alpha effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗