Lung Resistance Protein Research Articles

The clinical significance of P-glycoprotein, lung resistance protein and multidrug resistance related protein expressions in infiltrating breast carcinoma tissues

Our purpose was to explore clinical significance of three kinds of drug resistance related proteins, including P-glycoprotein (P-gp), lung resistance protein (LRP), multidrug resistance related protein (MRP) expressions in infiltrating breast carcinoma tissues. Flow cytometry was used to analyze the expression of drug resistance related proteins in carcinoma tissues and corresponding para-carcinoma tissues from 68 primary infiltrating breast carcinoma patients. The relative fluorescence intensity (RFI) expressed by median (M) of P-gp, LRP and MRP in breast carcinoma tissues were 0.58, 0.51and 0.56 respectively. In corresponding para-carcinoma tissues, their expression level were 0.26, 0.33 and 0.30. Their difference were obvious (P < 0.05). There were not notable differences of drug resistance related protein expressions in different ages, different tumor sizes, different pathological types, different clinical stages, estrogen receptor or progestin receptor negative and positive patients (P > 0.05). The expressions of P-gp and MRP in lymph node metastasis positive patients were 0.61and 0.69, in lymph node metastasis negative patients they were 0.54 and 0.45. There were no notable differences of P-gp and MRP expression in lymph node metastasis negative and positive patients. The expression of LRP (M = 1.49) was higher in lymph node metastasis positive patients than that in negative patients (M = 0.50, P < 0.05). The correlation analysis showed that there was positive correlation between the expression of LRP and MRP in breast carcinoma tissues (P < 0.05). The clinical significance of three kinds of drug resistance related protein expressions had differences in infiltrating breast carcinoma tissues. The expression of LRP had related with lymph node metastasis status and had positive correlation with MRP expression. It can become a target in forecasting breast carcinoma prognosis.

Expression of Multidrug Resistance 1, Lung Resistance Protein and Breast Cancer Resistance Protein Genes in Chronic Lymphocytic and Chronic Myelogeneous Leukemia.

One of the major problems in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents, which is already present at diagnosis or after chemotherapy as a minimal residual disease. The resistance may be originated from genetic or epigenetic mutations during prior growth of the leukemic clone. In this study, the expressions of three multidrug resistance (MDR) genes were investigated. Expression levels of multidrug resistance resistance gene 1 (MDR1), breast cancer resistance protein (BCRP) gene, and lung resistance protein (LRP) gene expression levels were determined in peripheral blood samples from 16 cases of chronic lymphocytic leukemia (CLL) and from 23 cases of chronic myelogeneous leukemia (CML) using RT-PCR. The expression of each of these genes was then expressed as a ratio in relation to β2-microglobulin gene expression in densitometric measurements. MDR1, BCRP and LRP expression levels was detected in 56,3%, 18,8% and 50% of CLL patients, respectively, with no difference for stage or response to the treatment. Four out of 16 (25%) CLL patients expressed none of these genes. The other 25% CLL patients expressed all of these genes. MDR1, BCRP and LRP expression was detected in 47,8%, 39,1% and 30,4% of CML patients, respectively, with no difference for progression or response to imatinib mesylate. Eight out of 23 (34,8%) CML patients expressed none of these genes. Four out of 23 (17,4%) CML patients expressed all of these genes, and two out of whom rapidly progressed to acute leukemia and unresponsive to the treatment. In conclusion, MDR and LRP overexpression seems to be a frequent event in CLL and CML patients; however no conclusion can be drawn on their prognostic role and response to the treatment.

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status

The proteasome inhibitor bortezomib may be effective in combination with cytarabine and anthracyclines in the treatment of acute myeloid leukemia (AML) by virtue of targeting aberrantly activated NF-kappaB in AML stem cells. We tested whether bortezomib cytotoxicity is affected by multidrug resistance (MDR) proteins expressed in AML cells. We also tested whether bortezomib interactions with cytarabine and anthracyclines are affected by p53, because proteasome inhibition stabilizes p53 and may thus cause cell cycle arrest. Bortezomib sensitivity of cell lines overexpressing P-glycoprotein, multidrug resistance protein-1, breast cancer resistance protein and lung resistance protein was studied in the presence and absence of established modulators of these transport proteins. Drug interactions during simultaneous and sequential exposure to bortezomib and anthracyclines or cytarabine in diverse ratios were evaluated by isobologram and combination index analyses in AML cell lines with wild type and inactive p53 and were correlated with cell cycle perturbations induced by bortezomib. Of the MDR mechanisms studied, only P-glycoprotein conferred resistance to bortezomib, and resistance was only twofold. Interactions between bortezomib and anthracylines and cytarabine changed from antagonistic to additive or synergistic with increasing drug activity levels and were not affected by p53 status. MDR proteins and p53 do not affect bortezomib cytotoxicity or in vitro interactions with anthracyclines or cytarabine, but these interactions are concentration-dependent, and this concentration-dependency should be considered in the design of combination regimens.

Differential Expression of P-Glycoprotein, but Not of MRP, LRP and BCRP in Leukemic Stem Cells Compared to More Differentiated CD34+ CD38+ Acute Myeloid Leukemia Blasts.

The identity and nature of the leukemic stem cell (LSC) is an area of intense research interest since it may lead to a better understanding of the leukemogenic process and development of specific therapies. By definition, the LSC retains the stem cell properties of self-renewal, high proliferative capacity, predominant quiescent cell cycle status and differentiation potential, and is biologically distinct from more differentiated blasts. Here we address the question whether the expression of membrane transporters associated with multidrug resistance (MDR) phenotype is differentially expressed in LSC (defined as CD34+,CD38−CD123+) and more mature blasts CD34+CD38+ and the bulk leukemic population. Twenty-one patients with AML de novo were selected based on CD34 positivity by the leukemic blasts. MDR protein expression was measured by flow cytometry with the monoclonal antibodies against P-glycoprotein (P-gp), MDR-related protein (MRP), Lung-resistance protein (LRP) and breast cancer resistance protein (BCRP). In all experiments, at least one hundred thousand events were acquired in a FACScalibur flow cytometer and analysis was performed using the Cell Quest software. The expression levels of MDR transporters were analyzed using:the Kolmogorov-Smirnov test, categorizing D value for descriptive purposes as high if D ≥ 0.30, low if 0.2 ≤ D < 0.3 and negative if D < 0.20; andthe mean channel fluorescence index (MFI), defined by the difference between the mean channel of fluorescence (MCF) for each antigen and MCF of the respective isotypic control.LSCs represented 0.33% (0.01–3.13%) of the total population of leukemic blasts. The values of D and MFI for MRP, LRP and BCRP in LSC, CD34+CD38+ and bulk leukemic population were not statistically different. In contrast, D values for P-gp were higher in LSCs (the mean ± Standard Error: 0.71 ± 0.10) compared to bulk leukemic population (0.38 ± 0.10, P=0.004) and to the CD34+CD38+ (0.21 ± 0.04, P=0.05) subset. In agreement, MFI values for P-gp were 146.7 ± 66.1, 38.2 ± 11.0 and 62.78 ± 16.4 in LSCs, blasts, and CD34+CD38+ respectively. Based on the LSC analysis, 95%, 85% and 57% of AML cases were found to have high expression (D ≥ 0.3) of MRP, LRP and BCRP, respectively. Similarly, 95%, 86% and 62% of the patients were thus categorized when the bulk population and 100%, 95% and 62% when CD34+CD38+ subsets were analyzed. Our results demonstrate that P-gp is overexpressed in LSCs compared to more differentiated subsets. Considering that P-gp-mediated drug efflux is the best characterized cellular mechanism of MDR, its constitutively high expression in LSCs may protect them from genotoxins and provide survival advantage. In addition, its conceivable that previously described higher incidence of MDR phenotype at relapse may reflect the selection of an intrinsic MDR+ LSC clone.

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.

Multidrug Resistance Proteins Overexpression Worsen the Favorable Clinical Impact of an Elevated Spontaneous Apoptosis in Acute Myeloid Leukemia (AML).

Multidrug resistance (MDR) proteins (P-glycoprotein [PGP], lung resistance protein [LRP], multidrug related protein [MRP]) and apoptosis proteins (bcl-2, bcl-xl, bax) expression represent key mechanisms explaining the high rate of treatment failure in AML, as demonstrated also by gene expression profiling studies (Wilson CS et al, 2006). Therefore, from 1995 to 2006, a large series of 386 AML de novo pts, median age 58 years, treated with intensive chemotherapy regimens, was tested. The principal aims of our study were:to demonstrate that bax/bcl-2 ratio and MDR are critical and independent events; andto clarify whether MDR is able to modify the favorable outcome of pts with high spontaneous apoptosis.PGP, LRP, MRP, bcl-2 and bax proteins were determined by multicolor flow cytometry. Concurrent positivity for PGP, LRP and MRP defined the MDR positive subset (n=112). There were significant correlations between immature FAB classes (M0–M1) and lower bax/bcl-2 ratio (83/128; p<0.00001) or monocytic differentiation (M4-M5) and higher PGP expression (133/163; p<0.00001). A significant correlation was found between a higher PGP and a higher bax/bcl-2 ratio (153/224; p=0.02). MRP was more represented in pts with lower apoptosis (103/162; p=0.00005). A significant lower complete remission (CR) rate was found in pts with lower bax/bcl-2 ratio (41% vs 70%, p<0.00001) or higher MDR (35 % vs 74%, p<0.00001). Overall survival (OS) and disease free survival (DFS) were significantly shorter either in pts with lower bax/bcl-2 ratio (0% vs 20% at 3.5 years, p<0.00001; 0% vs 17% at 2.7 years; p=0.0001) or higher MDR (0% vs 27% at 2.5 years, p<0.00001; 5% vs 36% at 1.3 years; p=0.0001). Bax/bcl-2 ratio and MDR showed an additive prognostic impact, since higher bax/bcl-2 ratio plus lower MDR identified pts at better prognosis with regard to CR (89% vs 27%; p<0.00001), OS (41% vs 0% at 2.5 years; p<0.00001) and DFS (42% vs 0% at 1.2 years; p=0.0009). Noteworthy, also PGP, LRP and MRP showed an additive prognostic impact with regard to OS, since PGP+LRP+MRP+ pts (n=112) identified an AML subset (MDR) at worse outcome as compared to PGP+ or LRP+ or MRP+ alone (0% vs 7% or vs 6% or vs 3% at 2.5 years, respectively). In order to establish whether MDR overexpression is able to worsen the favorable clinical outcome of AML pts with elevated apoptosis levels, we analyzed the subgroup with higher bax/bcl-2 ratio (n=224). A lower CR rate was found in patients with higher MDR expression (47% vs 89%, p=0.0005). Equally, higher MDR expression was associated both with a shorter OS and DFS (5% vs 41% at 1.5 years, p<0.00001; 10% vs 42% at 1.3 years, p=0.003). The superior and independent prognostic value of bax/bcl-2 ratio over MDR proteins was confirmed in multivariate analysis with regard to CR (bax/bcl-2: p=0.0001; PGP: p=0.004), OS (bax/bcl-2: p=0.0001; LRP: p=0.02) and DFS (bax/bcl-2: p=0.0004; PGP: p=0.03; LRP: p=0.03). Therefore, low apoptosis and higher MDR in elevated apoptosis identify the two main different biologic AML subsets at worse prognosis. In fact, it has to be taken in account that the favorable prognostic impact of a higher bax/bcl-2 ratio may be greatly reduced by MDR positivity. Actually, we conclude that we have to focus future research and therapeutic strategies targeting in the first place apoptosis and then MDR proteins in AML.

Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins

We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP). Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear-cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP. CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 microM. Tacrolimus enhanced cellular drug uptake at 1 microM, but not at 0.08 microM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 microM, but was effective at its clinically achievable concentration of 0.25 microM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 microM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites. CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations.

Multidrug resistance in small cell lung cancer: Expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease

The aim of this study was to investigate the expression of multidrug resistance-associated proteins in metastatic small cell lung cancer (SCLC) cells correlated to cisplatin/etoposide chemotherapy response and the level of those proteins in relapsed disease. Samples were obtained by transbronchial fine needle aspiration biopsy (TBNA) of enlarged mediastinal lymph nodes in 17 patients. After cytological confirmation of SCLC, cells were stained by a panel of mAbs against internal epitopes of P-gp (JSB-1), MRP1 (MRPr1), LRP (LRP-56) and cytokeratin (MNF116) and analyzed by flow cytometry. We observed a significant negative correlation for better response rate to chemotherapy with individual expression of P-gp (r=-0.93, P<0.0001; Pearson correlation) and MRP1 (r=-0.78, P=0.0002; Pearson correlation) in chemo-naive SCLC cells and a non-significant correlation for LRP expression. P-gp and MRP1 expression was markedly increased in metastatic cells in four out of five patients with relapsed disease (4-12 months after starting chemotherapy), in comparison to their chemo-naive values. In conclusion, the results suggest that P-gp and MRP1 might be associated with SCLC cell survival during metastasis and chemotherapy, and that overexpression of those transporters in relapsed disease could assist short-term chemotherapy efficiency.

Stromal cells extracted from ovarian cancer express functional multi drugs resistance proteins: ATP bindig casset and Major vault protein

2072 Background: Stromal cells play a central role for the growth of tumor cells. The functional contribution of these cells in cancer therapy is poorly understood. Here we studied the presenceofthe proteins ABC (ATP binding Cassette) and MVP (Major vault protein) implicated in the multi drugs resistance (MDR) phenomena in stromal cells isolated from ascitis of patients with ovarian carcinoma. Methods: Stromal cells were extracted from ascitis of patients with ovarian carcinoma. The expression of MDR proteins as p-gp (Permeability-glycoprotein), BCRP (breast cancer resistance protein) and MRPs (multidrug related proteins) as well as LRP (lung resistance protein that is a MVP) was studied by two different technique (immunocytochemistry and flow cytometry) using specific antibodies against these proteins. The functionality of the pumps or efflux, was studied by incorporation of fluorescent probes, Rhodamine 123 and JC1, substrate for p-gp, calcéine-AM substrate for p-gp and MRPs and at last Mitoxantrone substratum of BCRP, in the presence of specific inhibitors: as the cyclosporine HAS, the GG918 and the MK571 for the pumps Pgp, BCRP and MRPs respectively. Then the expression of the genes was assessed by RT-PCR. Results: 1) The expression of the proteins ABC is confirmed by immunocytochemistry and by flow cytometry. The Pgp and LRP proteins were strongly expressed and they are functional, the MRP-1, 2, 3 and BCRP proteins are weakly expressed and the MRP-5 protein is not detected. 2) The RNAm corresponding to all of these proteins is found by RT-PCR in the stromal cells. Conclusions: All of these results suggest that the MDR proteins are present on the cells surface of the tumour cell microenvironnement. The functionality of these proteins allows supposing their implication in the phenomena of multi drugs resistance to chemotherapy. The interaction between cancer cells and stromal cells should be targeted during specific chemotherapy. No significant financial relationships to disclose.

Effective therapy of experimental human malignant melanomas with a targeted cytotoxic somatostatin analogue without induction of multi-drug resistance proteins

Malignant melanomas are characterized by a high intrinsic resistance to chemotherapy. Multiple drug resistance (MDR) can be mediated by transport proteins such as MDR-1, multidrug resistance-associated protein (MRP) or lung resistance protein (LRP). The cytotoxic analogue of somatostatin AN-238 consisting of 2-pyrrolinodoxorubicin (AN-201) linked to a somatostatin analogue RC-121 binds to receptors for somatostatin and is targeted to tumors expressing these receptors. We evaluated the expression of somatostatin receptors on human malignant melanoma tumor lines MRI-H255 and MRI-H187 and examined the effects of the targeted analogue AN-238 and its cytotoxic radical AN-201 on growth of these tumors in nude mice. We also studied the effects of AN-238 and AN-201 on the expression of MDR-1, MRP-1 and LRP by real-time PCR. AN-238 inhibited the growth of MRI-H255 and MRI-H187 tumors while AN-201 was ineffective. Blockade of somatostatin receptors by somatostatin analogue RC-121 abolished the effects of AN-238. Targeted therapy with AN-238 did not produce an induction of mRNA of MDR-1, MRP-1 or LRP. Our findings show that targeted chemotherapy with cytotoxic somatostatin analogue AN-238 inhibits the growth of malignant melanomas. AN-238 could provide a novel treatment approach for advanced malignant melanomas.

Role of hypoxia-inducible factor-1α in formation of multidrug resistance induced by microenvironment in hepatocellular carcinoma

Objective: To explore the role of hypoxia-inducible factor-1α (HIF-1α) in formation of multidrug resistance (MDR) induced by microenvironment and to find a new and effective molecular target on preventing and reversing chemoresistance in hepatocellular carcinoma (HCC). Methods: In HepG2 cells exposed to hypoxia, low glucose or transfected by plasmid pcDNA3/HBX, the expression of HIF-1α mRNA and protein was respectively detected using real-time fluorescent quantitative PCR and Western blot technique and its expression localization was investigated by iinmunocytochemical technique. Plasmid pcDNA3/HIF-1α was transfected into HepG2 cells and then the expression of multidrug resistance related genes mdr1, multidrug resistance-associated protein 1 (MRP1) and lung resistance protein (LRP) in transfected cells was determined by the same methods. Results: In HepG2 cells respectively exposed to hypoxia, low glucose or transfected by plasmid pcDNA3/HBX, HIF-1α was overexpressed at mRNA and protein levels to varying degrees and translocated into nucleus. The gene expression levels of mdr1, MRP1 and LRP in HepG2 cells transfected by plasmid pcDNA3/HIF-1α were respectively increased by 2.4±0.2, 2.2±0.3 and 2.3±0.4 folds as compared with those in non-transfected HepG2 cells (all P0.01) and similar changes were observed in protein level. Conclusion: Microenvironmental factors around HCC could modulate the transcription of the MDR related genes by nuclear transcript factor HIF-1α, thereby conferred MDR of HCC. Up-regulation of HIF-1α expression could hold a central position in the formation of MDR of HCC induced by microenvironment. HIF-1α probably becomes a new and effective molecular target on preventing and reversing MDR in HCC.

Genes of multidrug resistance in haematological malignancies

Since the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.

The role of lung resistance protein in radiation treated head and neck carcinoma

Objectives. Vault proteins are ribonucleotide proteins composed largely of a single large protein termed major vault protein. (MVP) The (MVP) LRP gene is located on chromosome 16 close to the genes coding for multidrug resistance‐associated protein and protein kinase c‐β. The role of MVP (LRP) in cancer drug resistance has been demonstrated in various cell lines as well as in ovarian carcinomas and acute myeloid leukaemia, however little is known about its possible role in radiation resistance.1,2 Our aim was to examine this in head and neck squamous carcinoma (HNSCC). Method. One hundred and thirty three patients with proven squamous cell carcinoma of the oropharynx were recruited into the study, looking at two subsites of posterior tongue and tonsil. These patients received primary radiotherapy with curative intent. Archived biopsy material was obtained for 78 patients. Immunohistochemistry was used to detect LRP expression. Locoregional failure and cancer specific survival were estimated using Kaplan Meier method. Results. On analysis of the whole group together LRP expression was strongly associated with locoregional failure (P &lt; 0.0001) however, on subgroup analysis there was an obvious difference between the two sites, with increased LRP expression being associated with poor prognosis in the tongue group (P &lt; 0.0001), but not the tonsil group. (P = 0.14). Conclusion. This is the first reported study of LRP as a prognostic marker in radiotherapy treated HNSCC suggesting it may play an important role not just in cancer drug resistance but also in radiation resistance. Of added interest is the difference in prognostic significance between the two subsites. References 1 Scheffer G.L., Wijngaard P.L., Flens M.J., et al. (1995) The drug resistance‐related protein LRP is the human major vault protein. Nature Med.1, 578–5822 Kozlov G., Vavelyuk O., Ovidiu M., et al. (2005) Solution structure of a two‐repeat fragment of major vault protein. J. Mol. Biol.7

Expression dynamics of drug resistance genes, multidrug resistance 1 (MDR1) and lung resistance protein (LRP) during the evolution of overt leukemia in myelodysplastic syndromes

It is well-known that leukemic cells of overt leukemia (OL) that have transformed from myelodysplastic syndromes (MDS) are more resistant to chemotherapy as compared with de novo AML cells. Thus, to examine the expression levels of drug-resistant genes and their alterations with the development of OL in MDS, the expression of mRNA for MDR1 and LRP was determined in bone marrow samples from control, de novo AML, MDS, MDS at the time of OL transformation (MDS → OL), and after transformation (OL) by quantitative real-time RT-PCR. The expression of MDR1 in MDS bone marrow at the time of initial diagnosis was as low as that for control subjects. However, the expression level was significantly elevated at the time of the development of OL (MDS → OL) compared with the initial MDS subjects ( P < 0.05), while expression was relatively reduced after OL development (OL). The expression of LRP was significantly higher in MDS and MDS → OL samples than control subjects. However, the high expression of LRP in MDS → OL was significantly reduced after OL development (OL). The expression levels of drug-resistant genes in MDS → OL or OL were not significantly higher than those of de novo AML samples, although LRP expression in MDS or MDS → OL was relatively higher than that of de novo AML. Detecting increases in the expression of MDR1 would be useful for predicting OL development in MDS patients.

Study on the relationship among multidrug resistance factor expression of lung cancer tissues and clinicopathological characteristics in patients with lung cancer

Multidrug resistance (MDR) is not only the main reason of the failure of chemotherapy, but also the largest obstacle of the increase of survival rate in lung cancer. MDR of lung cancer is a complex procedure involved in multiple genes and mutiple pathways. Combined examination of resistance-related genes in lung cancer tissues has an important clinical significance. The aim of this study is to explore the relationship among the expression, coexpression of five multidrug resistance factors of lung cancer tissues and clinicopathological characteristics in patients with lung cancer. Immunohistochemical staining (EnVision method) was used to evaluated the expression of lung resistance protein (LRP), P-glycoprotein (P-gp), glutathione S-transferaseπ (GST-π), topoisomeraseII(TopoII), and multidrug-resistance-associated protein (MRP) in cancer tissues from 72 patients with lung cancer. The positive rate of LRP, P-gp, GST-π, TopoII and MRP was 79.2%, 86.1%, 54.2%, 29.2% and 30.6% respectively. There was a significant difference of the expression of LRP and TopoII in different sex (Chi-square=11.460 and 4.877, P=0.001 and 0.027), of the expression of LRP, GST-π and TopoII in NSCLC and SCLC (Chi-square=15.104, 14.076 and 9.409, P=0.001, 0.001 and 0.009), of the expression of GST-π in various grade of cell differentiation (Chi-square=8.933,P=0.011), of the expression of TopoII in various T staging (Chi-square=3.963,P=0.049). Spearman analysis of rank relativity showed that there was a better relativity between the expression of LRP, TopoIIand sex (r=0.464 and -0.205, P=0.000 and 0.027), between the expression of LRP, GST-π, TopoII and histology. The expression of LRP and GST-π was significantly higher in NSCLC than in SCLC (r=-0.390 and -0.262, P=0.000 and 0.018), the expression of LRP was significantly higher in adenocarcinoma than in squamous cell carcinoma (r =0.604, P=0.000). The expression of GST-π and TopoII was significantly higher in squamous cell carcinoma than in adenocarcinoma (r =-0.257 and -0.264, P=0.015 and 0.012). There was a reverse relativity between the expression of GST-π and cell differentiation (r =-0.232, P= 0.012 ). There was a positive relativity between the expression of TopoII and T staging (r =0.200, P= 0.031 ) and a reverse relativity between the expression of GST-π and T staging (r =-0.182, P=0.050). Spearman analysis of rank relativity of five multidrug resistance factors' coexpression showed that there was a positive relativity beween LRP and P-gp, LRP and MRP, P-gp and GST-π, P-gp and MRP, GST-π and MRP (r = 0.283 , 0.234, 0.453, 0.204 and 0.323, P=0.002, 0.011, 0.000, 0.027 and 0.000), the coexpression rate was 70.8%, 27.8%, 52.8%, 29.2%, 23.6% respectively. There was a reverse relativity between LRP and TopoII (r =-0.183, P=0.048), and the coexpression rate was 19.4%. The expression of partial multidrug resistance factors is relative significantly to sex, histology and cell differentiation, but not to T, N, M stage and clinical stage. The higher coexpression rate and positive relativity indicate MDR in lung cancer is affected by various multidrug resistance factors. It is important to detect coalescently various multidrug resistance factors.

IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes

Multidrug-resistant (MDR) multiple myeloma (MM) patients who fail chemotherapy frequently express MDR1 protein, which serves as an efflux pump that protects neoplastic cells. The expression of lung resistance protein (LRP), which mediates intercellular and nucleocytoplasmic transport, is also correlated with chemotherapy resistance and shorter survival of MM patients. Here, we investigated the chemotherapy-induced change of MDR expression in MM patients using quantitative RT-PCR. Overall expression levels of MDR1 and LRP in MM patients were significantly higher than those in control subjects and increased after chemotherapy. More than half of the patients exhibited increased expression of MDR1 (14/26) or LRP (17/26) after chemotherapy. Also, the expression of inhibitor of apoptosis proteins (IAP) was determined in association with the prognosis of the patients. Among patients with increased MDR1-expression after chemotherapy, those with a poor outcome exhibited significant increases in survivin, cIAP1, cIAP2, and XIAP expression by chemotherapy compared with those with a good prognosis. Similarly, in the LRP expression-increased group, patients with a poor outcome showed significant increases of cIAP1 and cIAP2 expression compared with those with longer survival. In patients with reduced-MDR1 or LRP expression after chemotherapy, changes in the expression of IAPs induced by chemotherapy did not correlate with their prognosis. These findings indicate that IAP family proteins might play a role in worsening the prognosis of MM patients in association with chemotherapy-induced overexpression of MDR1 or LRP.

Prognostic Significance of Multidrug Resistance Gene 1 (MDR1), Multidrug Resistance-related Protein (MRP) and Lung Resistance Protein (LRP) mRNA Expression in Acute Leukemia

The prognostic significance of multidrug resistance (MDR) gene expression is controversial. We investigated whether multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression are associated with outcomes in acute leukemia patients. At diagnosis we examined MDR1, MRP and LRP mRNA expression in bone marrow samples from 71 acute leukemia patients (39 myeloid, 32 lymphoblastic) using nested RT-PCR. The expression of each of these genes was then expressed as a ratio in relation to β-actin gene expression, and the three genes were categorized as being either 0, 1+, 2+ or 3+. MDR1, MRP and LRP mRNA expression was detected in 23.9%, 83.1% and 45.1%, respectively. LRP mRNA expression was significantly associated with resistance to induction chemotherapy in acute leukemia patients, and in the AML proportion (p=0.02 and p=0.03, respectively). MRP and high MDR1 mRNA expression was associated with poorer 2-yr survival (p=0.049 and p=0.04, respectively). Patients expressing both MRP and LRP mRNA had poorer outcomes and had worse 2-yr survival. The present data suggest that MDR expression affects complete remission and survival rates in acute leukemia patients. Thus, determination of MDR gene expression at diagnosis appears likely to provide useful prognostic information for acute leukemia patients.

Clinical and molecular differences between clear cell and papillary serous ovarian carcinoma

The aim of the current study is to compare clear cell ovarian carcinoma (CCOC) and papillary serous ovarian carcinoma (PSOC) with respect to their clinical features and expression of different regulators of cell cycle, apoptosis, and chemoresistance. Women with stage III CCOC (n = 9) and those with stage III, poorly differentiated PSOC (n = 21) seen between 1996 and 2000 and treated with cytoreductive surgery followed by paclitaxel and platinum chemotherapy were compared in their demographic features, tumor marker profile, surgical substage, results of cytoreductive surgery, thromboembolic complications, response to chemotherapy, and tumor recurrence. Tumor samples were compared in their expression of p53, Bcl(2), Bcl(x), Bax, p21, p-glycoprotein (PGP), multi-drug resistance-associated protein (MRP), lung resistance protein (LRP), and glutathione S-transferase (GST) using immunohistochemistry. Women with CCOC had significantly lower mean preoperative CA-125 values, lower surgical substage, less expression of p53, and more expression of p21 than women with PSOC (P = 0.037, 0.012, 0.008, and 0.009, respectively). Women with CCOC had less ascites, smaller amount of residual tumor, higher incidence of thromboembolism, chemoresistance, more expression of Bcl(2), and less expression of PGP than women with PSOC (P = 0.067, 0.078, 0.108, 0.114, 0.091, and 0.118, respectively). Women with CCOC exhibit certain clinical and molecular differences compared to stage- and grade-matched women with PSOC. Women with CCOC have a smaller tumor volume and manifest different expressions of p53, p21, and Bcl(2) than women with PSOC. Although further studies with larger number of patients are needed, our findings indicate that chemoresistance in CCOC is probably not p53-dependent.

Expression of P-glycoprotein, glutathione S-transferase-π, topoisomerase II and lung resistance protein in cardiac carcinoma and their clinical significances

Expression of P-glycoprotein, glutathione S-transferase-π, topoisomerase II and lung resistance protein in cardiac carcinoma and their clinical significances

Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia

An important problem in the treatment of children with acute lymphoblastic leukaemia (ALL) is pre-existent or acquired resistance to structurally and functionally unrelated chemotherapeutic compounds. Various cellular mechanisms can give rise to multidrug resistance (MDR). Best studied is the transmembrane protein-mediated efflux of cytotoxic compounds that leads to decreased cellular drug accumulation and toxicity. Several MDR-related efflux pumps have been characterised, including P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP). P-gp expression and/or activity has been associated with unfavourable outcome in paediatric ALL patients, whereas MRP1 and BCRP do not seem to play a major role. LRP might contribute to drug resistance in B-lineage ALL, but larger studies are needed to confirm these results. The present review summarises the current knowledge concerning multidrug resistance-related proteins and focuses on the clinical relevance and prognostic value of these efflux pumps in childhood ALL.