Clinical Study On The Correlation Of The Expression Of P-gp, MRP, LRP, GST-π And TopoⅡα And Chemotherapyresistance In Human NSCLC

Objective: Mechanisms of drug resistance of non small-cell lung cancer (NSCLC)are so complex, which involve multiple factors. One of the most important reasons isthe overexpression of some resistance-associated proteins. At present, the following fivekinds of resistance-associated protein: P-glycoprotein (P-gp), multidrug resistanceassociated protein (MRP), lung resistance-related protein (LRP),glutathione-s-transferase-π (GST-π) and topoisomerase IIα (TopoIIα), which werecommonly investigated, played an important role in drug resistance of NSCLC.Therefore, in this study, we analyzed the mRNA and protein levels expressions of thefive resistance-associated proteins in fresh lung cancer tissues by RT-PCR, western blotand immunohistochemistry. To investigate the relationship between the fiveresistance-associated proteins and drug resistance, the chemotherapy sensitivitycalculated by IC50of primary lung cancer cells to cisplatin, gemcitabine and paclitaxelin vitro were assayed according to the different pathological types of lung cancer cells.Methods: Primary lung cancer cells from16cases of thoracic surgery resection offresh lung cancer tissues (from October2010to June2011in the First AffiliatedHospital of Dalian Medical University) were isolated and assayed the expression ofP-gp, MRP, LRP, GST-π and TopoⅡα and the sensitivity of chemotherapy drugs ofcisplatin, gemcitabine and paclitaxel. The methylthiazo-letrazolium (MTT) was used toassay the three chemotherapy drugs to primary lung cancer cells by calculating the cellgrowth rate and drug resistance rate. Also the mRNA and protein expressions of the fiveresistance-associated proteins P-gp, MRP, LRP, GST-π and TopoⅡα in lung cancertissues and corresponding paraneoplastic tissues were assayed by RT-PCR, Westernblot and immunohistochemistry. Pearson correlation analysis was used to investigate the correlation between the cell growth rate and expressions of P-gp，MRP，LRP，GST-πand TopoⅡα, then its clinical significance were explored.Results:1. The five resistance proteins were expressed in the two pathologicaltypes and various stages of lung cancer tissues, but the levels were obviously different.For example, in adenocarcinoma, the expressions of LRP, P-gp were significantlyhigher than that in squamous cell carcinoma. And in squamous cell carcinoma, theexpressions of GST-π and TopoIIα were significantly higher than that inadenocarcinoma. The expression of GST-π was higher in well-differentiated lung cancerthan that in poorly differentiated cancer, whereas LRP was much higher in poorlydifferentiated cancer than that in well-differentiated tissues; in adjacent tissue the fivekinds of resistance proteins were expressed low or none.2. The chemotherapy sensitivityof the three drugs of cisplatin, gemcitabine and paclitaxel was various for differentpathological types and stages lung cancer. For adenocarcinoma, the sensitivity of thethree drugs was higher than that for squamous cell carcinoma; and for stage Ⅲ cancer,the sensitivity of the three drugs was higher than that for stagesⅠand Ⅱ.3. There werecorrelations between the expressions of the five resistance proteins and thechemotherapy sensitivity to cisplatin, gemcitabine and paclitaxel for the primary lungcancer cells.P-gp and LRP both showed a positive correlation to the resistance tocisplatin; TopoⅡα showed a positive correlation to gemcitabine, whereas GST-π andMRP both showed a negative correlation to the resitance to paclitaxel in lung cancer.Conclusions: The drug-resistance related proteins such as P-gp、MRP、LRP、GST-π and TopoIIα had different expression levels for lung cancer in different types,different stages and different differentiation degrees, and their expressions were relatedto the sensitivity of chemotherapy of cisplatin, gemcitabine and paclitaxel. Clinically,sensitive chemotherapy drugs can be selected according to the assays of drug sensitivityand expression of the drug-resistant related proteins. All the assays may be not onlybeneficial to revealed the nature of lung cancer but also conducive to formulate correctchemotherapy regimens to enhance the curative effect of chemotherapy and improvedthe prognosis.