A Study On The Expression Of Lung Resistance Protein And P-glycoprotein In Primary Epithelial Ovarian Cancer And Its Clinical Significance

The primary factor that limits the success of chemotherapy in ovarian cancer is the emergence of drug resistance in the tumor cell population. Results of treatment in response to chemotherapy and survival have steadily improved over the years following the cytoreductive surgery followed by the administration of intensive platinum/paclitaxel-based combination chemotherapeutic regimens. Still, the pathological complete remission and a 5-year survival rate remain approximately 20-40% and 10-20% for patients with advance stage disease. A very intriguing development in drug resistance research is the discovery of the phenomenon of multidrug resistance(MDR). MDR describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Once tumor cells are resistant to a single drug, they appear cross resistance to a wide range of drugs.P-glycoprotein(P-gp), a transmembrane transport protein, is the earlier identified resistance mechanisms, related to classical MDR. Transfer MDR1 cDNA to drug-sensitive cells has showed high level P-gp, resulting in MDR. These results have determined that P-gp expression confers to MDR. P-gp is encoded by MDR1 gene, localized to the 7q21.1 chromosomal segment. Its molecular weight is 170KD. Theprotein, 1280 amino acids long, consists of two homologous parts of approximately equal length. Each half of the protein includes a hydrophobic region with six predicted transmembrane segments and a hydrophilic region. The hydrophilic regions share homology with peripheral membrane components of bacterial active transport systems and include potential nucleotide-binding sites. P-gp acts as an energy dependent unidirectional drug efflux pump with broad substrate specificity. It uses energy in the form of ATP to transport drugs, thus, reducing drug accumulation and resulting drug resistance. In many normal tissues, P-gp is thought to act as a detoxifying agent by pumping toxins including anticancer drugs out of cells. In other organs, such as the adrenal gland and the gravid uterus, it may transport steroid hormones. Increased levels of P-gp are common in cancer cells. The presence of increased levels of P-gp in several types of tumor has been correlated with poor response to chemotherapy and short overall survival.The lung resistance protein(LRP) is a newly described protein related to MDR. Because it was first identified in lung cancer multidrug resistance cell line SW-1573/2R120, it is called lung resistance protein. Transfer of the non-P-gp MDR phenotype to sensitive parental cells by cell fusion also has resulted in MDR, showing drug accumulation defects. The reversal of drug resistance results in the decrease of LRP expression, indicating the close relation between LRP expression and drug resistance. LRP is encoded by LRP gene, localized to the 16P13.1-16P11.2 chromosomal segment. Its molecular weight is 110KD. It is identified as the human major vault protein. Vaults are novel cellular organelles, which are thought to mediate intracellular transport of a wide variety of substrates. LRP is widely distributed in normal human tissues and tumors, suggesting an unique role for vaults in normal and malignant cells. The clinical pathological study in establishment of LRP as a marker of clinical drug resistance has been performed in malignant tumors. It has been reported that LRP expression is significantly associated with poor response to chemotherapy and short survival in patients with primary epithelial ovarian cancer(PEOC).Up to now, the reports about correlation between expression of LRP or P-gp andpatients' prognosis are conflicting.To investigate the association between LRP or P-gp expressions and prognosis, in the present study, the expressions of LRP and P-gp in paraffin embedded 64 cases of PEOC were determined by using SP immunohistochemical staining and the results were studied in correlation with some clinical and pathological features and prognosis. The exp...