Expression Of Multidrug Resistance Proteins In Non-small Cell Lung Cancer: Association With Chemotherapeutic Response And Prognosis

Background and ObjectivesLung cancer is a major cause of death from cancer worldwide and non-small cell lung cancer (NSCLC) accounts for 75% of all lung cancer cases. More than half of NSCLC are advanced stage IIIB or IV disease at diagnosis, and patients with advanced NSCLC are candidates for systemic chemotherapy. Intrinsic or acquired tumor-mediated drug resistance is a major clinical problem that can result in the deficiency of chemotherapy. P-gp(p-glycoprotein), MRP1(multidrug resistant protein1) and BCRP (breast cancer resistant protein) belong to the ATP-binding cassette transporter superfamily, act as energy-dependent efflux pumps, can decreasing the intracellular drugs concentration.In vitro selection for resistance to a single chemotherapeutic agent often results in cross-resistance to various structurally and functionally dissimilar drugs, a phenomenon called multidrug resistance (MDR). Several mechanisms have been described in MDR, such as overexpression of P-gp, MRP1 and BCRP. In vitro overexpression of P-gp can confer resistance to abroad range of natural product drugs, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, paclitaxel and alkylation. The drugs specificity of MRP1 initially seemed to be similar to that of P-gp, but thus far, MRP1 transports paclitaxel relatively poorly. Elevated expression of BCRP in vitro causes resistance to anticancer drugs, including topotecan, irinotecan, SN-38, mitoxantrone, and doxorubicin but not to vincristine, paclitaxel and cisplatin.In this retrospective study, we investigated the level of expression of BCRP, in addition to Pgp, MRP1 and MRP3, in clinical samples of NSCLC, and investigated whether its expression predicts response to chemotherapy and prognosis.Materials and MethodsA total of 66 tissue samples from untreated NSCLC patients at the Henan Province Tumor Hospital from 2003 to 2005, at the PS 0 or 1 on the Eastern Cooperative Oncology Group scale are studied here, of which 34 were obtained in the surgery, others from bronchoscopy. Expression of ABC transporter proteins, including P-gp, MRP1 and BCRP, was examined immunohistochemically in all formalin-fixed tumor samples. Normal lung tissue human was used as a negative control. All of the slides were examined and scored independently by two observers without knowledge of the patient clinical data. The histological classification was based on a WHO report. Clinical staging was based on an initial evaluation consisting of a clinical assessment, chest radiography, computed tomography of the chest and abdomen, computed tomography or magnetic resonance imaging of the brain, and bone scintigraphy, according to the current international staging system. Their median age at diagnosis was 56 years (range, 35-75 years). All of the stage IIIB or IV patients were treated with platinum-based combination chemotherapeutic regimens, which were considered to be standard regimens for patients with metastatic NSCLC. The median follow-up time of the 66 patients was 311 days (range, 31-759 days).The correlations among immunohistochemical expression and the clinical variables and response to chemotherapy were evaluated by the univariate and multivariate logistic regression analyses. Overall survival was measured from the start of chemotherapy to the date of death from any cause or the date the patients were last known to be alive. Survival curves were estimated by the Kaplan-Meier method, and differences in survival between subgroups were compared by using the log-rank test. The correlation between variables affecting survival was evaluated by multivariate Cox proportional hazards model. P<0.05 were considered significant. Two-sided statistical tests were used in all of the analyses. Statistical analysis software (SAS8.1) was used for the analyses.Results 1. Expression of ABC Transporter Proteins in NSCLC.P-glycoprotein, multidrug resistance protein 1 and breast cancer resistance protein were highly expressed in 40.91% 72.73% and 43.94% of all cases, respectively.P-gp expression was associated with gender age smoking and histology. MRP1 expression was significantly greater in adenocarcinoma than in squamous cell carcinoma. There were no significant correlations between BCRP expression and the clinic pathological features.2. Expression of ABC Transporter Proteins and Clinical Outcome.P-gp, MRP1 and BCRP were examined immunohistochemically in 32 cancer samples from untreated patients with NSCLC in stage III or IV who subsequently received platinum-based chemotherapy. Their response to chemotherapy was studied in relation to the expression of each of these multidrug resistance proteins. Only BCRP expression was associated with response to chemotherapy. No significant associations were found among expression of Pgp and MRP1 in response to chemotherapy.3. Multivariate Analysis for Overall Survival.Significant associations were found among the patient's overall survival time and Pgp and MRP1 co-expression, as well as the stage. The overall survival time was associated with the TNM stage and P-gp expression in the adenocarcinoma group.Conclusion1. Positive immunostaining for BCRP appears to be a predictor of response to chemotherapy in patients with advanced NSCLC. These findings indicate that BCRP may serve as a molecular target for reducing drug resistance to chemotherapy in advanced NSCLC patients.2. Increased expression of P-gp and MRP1 appears to be a predictor of prognosis in NSCLC patients, whereas BCRP expression was not associated with prognosis.