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PubMed2002

In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Serological and proteomic evaluation of antibody responses in the identification of tumor antigens in renal cell carcinoma.

Renal cell carcinoma (RCC) is relatively resistant to conventional chemotherapy and radiotherapy. However, reports of spontaneous regression along with promising results in clinical trials suggest that immunotherapuetic strategies may be of clinical benefit. Few RCC related antigens have been identified to date, and the technical difficulty and time constraints of current antigen identification techniques preclude the screening of large numbers of patients. A comparatively rapid strategy has been used to identify components of tumors that elicit an antibody response in the patient - the serological and proteomic evaluation of antibody responses (SPEAR) approach. This combines two-dimensional polyarylamide gel electrophoresis of tumor and normal kidney samples with immunoblotting using autologous patient sera and protein identification by mass spectrometry. Using the SPEAR approach to screen RCC patients for naturally occurring antitumor antibody responses, a number of candidate immunogens have been identified in patients with high-grade disease and their relative expression levels in tumor tissue compared to normal tissue have been studied. These proteins include annexins I and IV, thymidine phosphorylase (TP), carbonic anhydrase I, Mn-superoxide dismutase and major vault protein (MVP). Downstream analysis of the tissue expression of some of these proteins shows that MVP is up-regulated in 2/4 of RCC tumors but is also expressed in normal kidney whereas TP is up-regulated in 100% (11/11) of RCC cases examined with no or minimal expression in normal kidney, indicating a potential use as a therapeutic target.

Annexins↗
PubMed2000

Cloning and initial analysis of the human multidrug resistance-related MVP/LRP gene promoter.

The lung resistance-related protein (LRP) was identified as the human major vault protein (MVP), and is overexpressed in various multidrug-resistant cancer cell lines and clinical samples. We characterized DNA sequences upstream to the transcription initiation site of the MVP gene in the human non-small cell lung cancer cell line SW-1573. A 1.9-kb and a shortened 0.7-kb fragment of the 5'-upstream genomic region show strong promoter activity in chloramphenicol acetyltransferase (CAT) reporter assays. The promoter is TATA-less and contains an inverted CCAAT-box and a Sp1 site located near to a p53 binding motif. An alternative 3'-splice site of intron 1 results in a splicing variant within the 5'-untranslated region of MVP mRNA.

5' Untranslated Regions↗
PubMed2002

Structural domains of vault proteins: a role for the coiled coil domain in vault assembly.

Vaults consist of multiple copies of three proteins (MVP, VPARP, and TEP1) and several untranslated RNAs. The function of vaults is unknown but the typical and evolutionary conserved structure indicates a role in intracellular transport. Although all vault components have been identified and characterized, not much is known about vault protein assembly. In this study we identified and analyzed structural domains involved in vault assembly with emphasis on protein-protein interactions. Using a yeast two-hybrid system, we demonstrate within MVP an intramolecular binding site and show that MVP molecules interact with each other via their coiled coil domain. We show that purified MVP is able to bind calcium, most likely at calcium-binding EF-hands. No interactions could be detected between TEP1 and other vault proteins. However, the N-terminal half of MVP binds to a specific domain in the C-terminus of VPARP. Furthermore, VPARP contains amino acid stretches mediating intramolecular binding.

Amino Acid Sequence↗
PubMed2001

Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma.

OBJECTIVE: Preliminary studies have suggested that lung resistance protein (LRP), multidrug resistance protein (MRP), and p27 may be useful markers of chemoresistance. Our goal was to evaluate the expression of LRP, MRP, and p27 in normal ovaries and chemosensitive and chemoresistant ovarian carcinomas. METHODS: Fourteen women with normal ovaries and fifty women with epithelial ovarian carcinoma who underwent cytoreductive surgery from 1996 through 1998 had specimens stained with immunocytochemistry for LRP, MRP, and p27. All women received paclitaxel/platinum-based chemotherapy. Twenty-nine women had a disease-free survival (DFS) of at least 12 months after completion of chemotherapy (sensitive) and 21 women had persistent disease during treatment (resistant). RESULTS: Evaluation of LRP expression revealed significant differences between the normal ovaries and cancers in both the epithelial (57% vs 90%, P = 0.03) and stromal (86% vs 32%, P = 0.001) components. Evaluation of MRP expression revealed significant differences between normal ovaries and cancers in the epithelial component (7% vs 66%, P = 0.001) but not in the stromal component (14% vs 4%, P = 0.1). Evaluation of p27 revealed significant reductions in expression in cancers compared with normal ovaries for both the epithelial (90% vs 55%, P = 0.02) and stromal (88% vs 5%, P = 0.001) components. Comparison between the chemosensitive and chemoresistant groups revealed no significant differences in expression of LRP and MRP, in either the epithelial or stromal component, but significantly lower levels of p27 were expressed in the epithelial component of the chemoresistant group (P = 0.01). CONCLUSIONS: The expression of LRP, MRP, and p27 is significantly different in ovarian cancers compared with normal ovaries. Low levels of p27 expression are associated with chemoresistance; however, LRP and MRP expression are not prognostic for chemosensitivity.

ATP-Binding Cassette Transporters↗
PubMed1997

Do cMOAT (MRP2), other MRP homologues, and LRP play a role in MDR?

The discovery of the Multidrug Resistance-associated Protein (MRP or MRP1) as a GS-X pump able to transport both anionic drug conjugates and unmodified anti-cancer drugs out of the cell, has raised the question whether other members of the MRP family might contribute to drug resistance of human tumours. The most extensively studied member of this family is cMOAT, the canalicular Multispecific Organic Anion Transporter. The substrate specificity of this pump was originally defined by an inborn error in rats, lacking this protein. These rats are mildly hyperbilirubinemic, because of their inability to secrete bilirubin glucuronides into their bile. In addition, they have diminished capacity to secrete a variety of other organic anions. Absence of cMOAT in humans results in an analogous inborn error of metabolism, the Dubin-Johnson syndrome. Attempts to determine the effect of cMOAT on the sensitivity of cells to anti-cancer drugs have run into technical problems. Most cells transfected with a cMOAT cDNA construct and overproducing cMOAT seem unable to transport the protein to the cell surface and are not MDR. However, in polarized kidney cell monolayers cMOAT is correctly routed to the apical cell surface and able to transport vinblastine. Hence, overexpression of cMOAT in cancer cells could potentially lead to drug resistance. In studies of cells selected for drug resistance no correlation was found thus far between cMOAT overexpression and MDR, but there was a positive association with cisplatin resistance, raising the possibility that cMOAT might contribute to cisplatin resistance by mediating excretion of cisplatin-glutathione complexes. This remains to be verified by more direct experiments and clinical studies, however. Database searches have yielded four additional MRP family members, MRP3-6. The physiological functions of these putative transporters are not yet known and whether they can contribute to drug resistance needs to be determined. Another putative transporter found in many MDR cells not overproducing P-glycoprotein is the Lung Resistance Protein (LRP), which is the major vault protein. Scheper et al have detected LRP in many MDR cell lines and they have shown that elevated LRP values are a strong and independent predictor of unfavourable outcome for several types of drug-treated human tumours. LRP is a cytoplasmic protein and attempts to demonstrate its involvement in drug transport have failed thus far. The possibility that this protein is only an indicator of resistance caused by upregulation of other proteins, rather than a drug transporter, remains open.

ATP-Binding Cassette Transporters↗
PubMed2000

Low-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distribution.

The P-glycoprotein (P-gp)-negative epidermoid pharyngeal carcinoma cells KB-3-1 were grown in 0.25 mM benzo[a]pyrene (BaP) for 3 months and increased resistance to doxorubicin, but not to vinblastine, colchicine, or cisplatin, was found. Doxorubicin resistance was not altered by cyclosporin, the P-gp inhibitor. Intracellular accumulation of BaP or calcein, a substrate for P-gp and multidrug resistance protein (MRP), was not altered by inhibitors of the P-gp and MRP. The expression of cytochrome P450 (CYP) 1A1, lung-resistance-related protein (LRP), P-gp, and MRP was investigated. Overexpression of CYP1A and LRP, on the mRNA and protein levels, was found. BaP-treated KB-3-1 cells remained P-gp negative while the level of MRP was not altered. Subcellular accumulation of BaP was found to be localized in the cytoplasm and minimal in the nuclei in BaP treated cells. In contrast, even penetration of BaP to the nuclei and cytoplasm was found in untreated cells. Subcellular distribution of doxorubicin was altered following BaP treatment with localized accumulation of the cancer drug in cytoplasmic organelles but not in the nuclei. Our data suggested that LRP might play a protective role against toxic compounds. The correlation of increased expression of LRP, but not P-gp nor MRP, with decreased doxorubicin accumulation in the nuclear target suggests a pivotal role of this perinuclear transporter in the MDR phenotype of P-gp-negative cancer cells. These results also propose an alternative mechanism of cancer drug resistance emergence, namely, induction of LRP activity following treatment with BaP, an environmental toxicant and a carcinogen.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

The lung resistance protein (LRP) predicts poor outcome in acute myeloid leukemia.

To determine the clinical significance of the lung resistance protein (LRP) in acute myeloid leukemia (AML), we have studied LRP expression of leukemic blasts and its association with clinical outcome in patients with de novo AML. LRP expression of leukemic blasts was determined by immunocytochemistry by means of monoclonal antibody LRP-56. LRP expression at diagnosis was detected in 31 out of 86 (36%) patients and correlated with white blood cell count (p = 0.01). The complete remission rate of induction chemotherapy was 72% for all treated patients (n = 82). The complete remission rate was 81% for patients without LRP expression but only 55% for patients with LRP expression (p = 0.01). Overall survival and disease-free survival were estimated according to Kaplan-Meier in 82 and 59 patients, respectively. At a median follow-up of 16 months, median overall survival was 17 months for LRP-negative patients but only 8 months for LRP-positive patients (p = 0.006). Disease-free survival was 9 months for LRP-negative patients and 6 months for LRP-positive patients (p = 0.078). Thus LRP predicts for poor outcome indicating that the LRP gene is a clinically relevant drug resistance gene in AML.

Adolescent↗
PubMed1999

Histopathological assessment of multidrug resistance in gastric cancer: expression of P-glycoprotein, multidrug resistance-associated protein, and lung-resistance protein.

Because local recurrence is common after a curative resection for advanced gastric cancer, there has been significant interest in adjuvant chemotherapy. However, the overall effect of chemotherapy remains debatable regarding patients with advanced gastric adenocarcinoma. Multidrug resistance is thought to be a major cause of failure in cancer chemotherapy, and thus the expression of P-glycoprotein (P-Gp), multidrug resistance-associated protein (MRP), and lung-resistance protein (LRP) in tumor cells was evaluated by immunohistochemistry. In 20 gastric adenocarcinomas, 11 (55%), 2 (10%), and 0 (0%) were positive for MRP, LRP, and P-Gp. In malignant lymphomas, only 3 out of 10 cases were positive for MRP (30%). The positive rate of MRP staining was significantly higher in well and moderately differentiated adenocarcinomas (80%) than in poorly differentiated adenocarcinomas (20%). With regard to the degree of MRP expression and histological cell type, higher grades (grade 2-3) were observed only in well and moderately differentiated adenocarcinomas. In terms of the positive-stained cells and staining intensity, heterogeneity was observed in the staining profile of MRP. The proliferative cell nuclear antigen labeling index (PCNA LI) of MRP-positive and MRP-negative cases was 49.3% +/- 11.6% and 49.4 +/- 6.9%, respectively. No correlation was observed between the MRP expression and PCNA LI. In conclusion, the incidence of MRP expression in gastric cancer was the highest in three different multidrug resistance-related epitopes. An evaluation of the MRP expression thus seemed to be beneficial for determining the optimal strategy of chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

The association of increased lung resistance protein expression with acquired etoposide resistance in human H460 lung cancer cell lines.

Chemoresistance remains the major obstacle to successful therapy of cancer. In order to understand the mechanism of multidrug resistance (MDR) that is frequently observed in lung cancer patients, here we studied the contribution of MDR-related proteins by establishing lung cancer cell lines with acquired resistance against etoposide. We found that human H460 lung cancer cells responded to etoposide more sensitively than A549 cells. Among MDR-related proteins, the expression of p-glycoprotein (Pgp) and lung resistance protein (LRP) were much higher in A549 cells compared with that in H460 cells. When we established H460-R1 and -R2 cell lines by progressive exposure of H460 cells to increasing doses of etoposide, the response against etoposide as well as doxorubicin was greatly reduced in R1 and R2 cells, suggesting MDR induction. Induction of MDR was not accompanied by a decrease in the intracellular accumulation of etoposide and the expression of MDR-related proteins that function as drug efflux pumps such as Pgp and MRP1 was not changed. We found that the acquired resistance paralleled an increased expression of LRP in H460 cells. Taken together, our data suggest the implicative role of LRP in mediating MDR in lung cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Expression of lung resistance-related protein, LRP, and multidrug resistance-related protein, MRP1, in normal human lung cells in long-term cultures.

Transport processes form part of the body's defense mechanism, and they determine the intracellular levels of many endogenous and exogenous compounds. The multidrug resistance-related protein MRP1 and the lung resistance-related protein LRP are associated with drug resistance against chemotherapeutics; they protect cells against toxic compounds. There is much experimental evidence to suggest that both of these transporter proteins serve important physiological functions. The expression of LRP and MRP1 was studied in normal human bronchial epithelial cells (NHBEC) and peripheral lung cells (PLC) obtained from explant cultures from morphologically-normal human lung tissue taken from patients with lung cancer. LRP (mRNA and protein) was detected in the cells of the bronchi as well as the peripheral lung with low (a factor of 2.6) inter-individual variation in the first generation. No significant alterations were noted for LRP within three-to-four generations in the same patient. LRP expression was not substantially different between cultures from different topographic regions of the human lung. MRP1 protein and MRP1 mRNA could also be detected in all of the NHBEC and PLC cultures studied, but with substantially higher (a factor of 7.7) intra-individual variation in the first generation than for LRP. MRP expression was the same for bronchial cells and PLC when the material was obtained from both sites. The level of mRNA for MRP1 was, in general, less stable than that for LRP. In multigeneration explant cultures, the levels of LRP mRNA and protein and MRP1 protein did not fluctuate greatly, but the level of MRP1 mRNA dropped to about 25% of the reference value within four generations (after about 8-10 weeks of culture). In one case, NHBEC subpassages were followed over a period of 20 weeks. In this system MRP mRNA levels increased by more than threefold, while levels of MRP1 protein and LRP mRNA and protein were expressed at almost constant rates.

Adult↗
PubMed2003

Using technetium-99m tetrofosmin chest imaging to predict taxol-based chemotherapy response in non-small cell lung cancer but not related to lung resistance protein expression.

In vitro studies have shown that technetium-99m tetrofosmin (Tc-99m TF) is a transport substrate for the P-glycoprotein (Pgp) pump. Therefore, Tc-99m TF uptake of tumors can be used to predict chemotherapy response in lung cancers. However, whether lung resistance-related protein (LRP) expression affects tumor accumulation and efflux of Tc-99m TF in lung cancers is not known. Our aim was to use Tc-99m TF uptake of tumors to predict paclitaxel-based chemotherapy response of non-small cell lung cancer (NSCLC) and to compare Pgp or LRP expression. Twenty patients with advanced NSCLC received Tc-99m TF chest images before Taxol-based chemotherapy was used in this study. The chemotherapy response was evaluated by clinical and radiological methods in the third month after completion of treatment. No significant differences of prognostic factors (age, sex, body weight loss, performance status, tumor size, tumor stage, and tumor cell type) were found between the patients with good and those with poor responses. Early and delayed tumor/normal lung (T/L) uptake ratios were calculated on Tc-99m TF chest images. Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to detect Pgp and LPR expressions. The early and delayed T/L uptake ratios of 10 patients with good response were significantly higher than those of the other 10 patients with poor response. Significantly higher early and delayed T/L uptake ratios were found in patients with negative than those with positive Pgp expression ( p < 0.05). However, no significant differences of early and delayed T/L uptake ratios were found between patients with negative and positive LRP expressions ( p > 0.05). We found that Tc-99m TF imaging could accurately predict Taxol-base chemotherapy response. In addition, the Tc-99m TF tumor uptake was related to Pgp but not LPR expression in NSCLC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Comparing the relationship of Taxol-based chemotherapy response with P-glycoprotein and lung resistance-related protein expression in non-small cell lung cancer.

Our aim was to compare Taxol-based chemotherapy response of non-small cell lung cancer (NSCLC) with P-glycoprotein (Pgp) or lung resistance protein expression (LRP). Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to detect Pgp and LPR expressions in 40 patients with advanced NSCLC before Taxol-based chemotherapy. The chemotherapy response was evaluated by clinical and radiological methods in the third month after completion of treatment. No significant differences of prognostic factors (age, sex, body weight loss, performance status, tumor size, tumor stage, and tumor cell type) were found between the 20 patients with good and the 20 patients with poor responses. The incidence difference of positive Pgp expressions between good and poor responses was significant, however, the difference of LRP expression was not. We concluded that Taxol-based chemotherapy response of patients with NSCLC was related to Pgp but not LPR expression.

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

Comparison of chemotherapy response with P-glycoprotein, multidrug resistance-related protein-1, and lung resistance-related protein expression in untreated small cell lung cancer.

The aim of this study was to investigate the expression of P-glycoprotein (Pgp), multidrug resistance-related protein-1 (MRP1), and lung resistance-related protein (LRP) in response to chemotherapy in untreated small cell lung cancer (SCLC). Immunohistochemical analyses were performed on multiple nonconsecutive sections of biopsy specimens to detect Pgp, MRP1, and LRP expression in 40 patients with SCLC before chemotherapeutic induction. Response to chemotherapy was evaluated by clinical and radiological methods. The patients were divided into a good response group (n = 20) and a poor response group (n = 20). No significant differences in prognostic factors (Karnofsky performance status, tumor size, or tumor stage) were found between the two groups of patients. The difference in positive Pgp and MRP1 expressions between the good and poor response groups was significant. However, the difference in LRP expression was not significant. We conclude that chemotherapy response of patients with SCLC was related to either Pgp or MRP1 but not LPR expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Expression of drug resistance related proteins in sarcomas of the pulmonary artery and poorly differentiated leiomyosarcomas of other origin.

Sarcomas are known to develop resistance to current chemotherapeutic strategies, displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance include reduced cellular drug accumulation, drug detoxification as well as alterations in drug target specificity. In seven sarcomas of the pulmonary artery (SPA) and ten leiomyosarcomas of other origin, we studied the immunohistochemical expression of P-glycoprotein (P-gp), multidrug-resistance protein (MRP), lung resistance protein (LRP), metallothionein (MT) and topoisomerase IIalpha. Upregulation was found in tumour cells for P-gp but not for MRP in SPA and other leiomyosarcomas. Topoisomerase IIalpha was expressed at high levels in tissue of primary tumours as well as recurrent tumours. Both P-gp and topoisomerase IIalpha were present in numerous tumour-associated vessels. LRP was expressed at high levels in SPA but to a lesser extent in the other leiomyosarcomas. MT was expressed at low levels but was markedly present at the border of necrosis. The overall survival and the relapse-free survival did not correlate with the expression of these factors. There was no significant relationship between treated and non-treated patients with respect to the expression of the examined molecules. P-gp, but not MRP, may play a role in the development of drug resistance. P-gp, LRP and topoisomerase IIalpha contribute to drug resistance through expression in tumour-associated vessels. Unique high levels of topisomerase IIalpha reflect the high proliferation rate of these tumours. MT seems to serve as a detoxifying agent of metabolites at the border of necrosis. Our findings underline the fact that multiple factors contribute to chemoresistance and that examination of a spectrum of relevant molecules is probably necessary to plan the best therapy.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Markers of drug resistance in relapsing colon cancer.

PURPOSE: 5-Fluorouracil failure and drug resistance, which often occurs during chemotherapy, is still a great obstacle to the success of human colon cancer treatment. Thus, the comparative study of markers of drug resistance in cancer cells before and after chemotherapy may be extremely helpful in the selection of the appropriate chemotherapeutic drug in colon cancer patients who fail adjuvant treatment with 5-fluorouracil. In the present study we examined the differential expression of three multidrug resistance-related proteins (i.e., P-glycoprotein, MRP, and LRP) and of topoisomerase IIalpha in a series of 20 primary colon carcinomas and their recurrences. METHODS: All markers were determined at tissue level by three-step immunohistochemistry using appropriate monoclonal antibodies, and the markers' immunopositivity was quantified by image analysis. In addition, Feulgen stain was used for the assessment of nuclear DNA content of malignant cells at their primary location. RESULTS: Some degree of aneuploidy was detected in all primary carcinomas. The immunoexpression of the three multidrug resistance-related proteins did not change significantly, either qualitatively (positivity vs negativity) or quantitatively, after chemotherapy. On the contrary, the percentages of topoisomerase IIalpha-positive malignant cells were significantly increased in the tumour recurrences by comparison to their primary locations ( P=0.011). CONCLUSIONS: According to our results, increased topoisomerase IIalpha immunohistochemical expression appears to be part of the malignant cells' phenotype in recurrent colon cancers. Therapeutic options after failure of 5-fluorouracil-based treatment could therefore include appropriate topoisomerase IIalpha-targeted drugs.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Multidrug resistance markers P-glycoprotein, multidrug resistance protein 1, and lung resistance protein in non-small cell lung cancer: prognostic implications.

PURPOSE: The aim of this retrospective study was to comparatively investigate the expression of the three drug-resistance genes P-glycoprotein (P-gp), multidrug-resistance protein 1 (MRP1), and lung resistance protein (LRP), in non-small cell lung cancer (NSCLC) tissues, and to assess possible associations with clinicopathologic features. METHODS: Tumor specimens from 126 patients were analyzed by immunohistochemistry and, in selected cases, by reverse transcriptase polymerase chain reaction (RT-PCR), and data were statistically analyzed by SPSS. RESULTS: The mean expression levels of tumor tissues in the case of P-gp and LRP did not exceed the one of normal epithelia, while MRP1 was significantly enhanced in NSCLC. A weak association was observed between higher grading and P-glycoprotein expression (p <0.08) as well as lower grading and MRP1 expression in the case of adenocarcinoma (p <0.05). MRP1 levels were highest in TNM stage I and declined with advanced stage (p <0.03). A significant association was found between high MRP1 levels and longer overall survival (N =115, p <0.04), which was highly significant in the patient group never treated with chemotherapy (N =77; p <0.007). P-gp expression was enhanced in those patients who had received chemotherapy before surgery (p <0.05). CONCLUSIONS: Our data point towards a major role of MRP1 in the intrinsic treatment resistance of NSCLC and suggest, in addition, a significant activation of P-gp expression during chemotherapy.

ATP Binding Cassette Transporter, Subfamily B↗