The Expression Of ERCC1/RRM1 And The Correlation Between Cisplatin Combine Gemcitabine Chemotherapy Sensitivity And Prognosis In Non-small Cell Lung Cancer

【Background】Primary bronchogenic carcinoma also known as lung cancer,is one of the most malignant cancers in the world. Lung cancer poses a serious threat to human health. It is the leading cause of cancer death in our country,whose incidence is rising at an alarming rate. An estimated 50,000 new cases (330,000 in men and 170,000 in women)of lung cancer was diagnosed in 2005 in China. Only 15% of lung cancer patients are alive 5 years or more after diagnosis. The World Health Organization divides lung cancer into 2 major classes based on its biology, therapy, and prognosis: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer patients made up about 80% to 85% of total lung cancer patients. About over 80% have lost the chance of surgical therapy when diagnosed, so chemotherapy is the major treatment. The platinum combined with gemcitabine chemotherapy regimens is the standard first-line chemotherapy for advanced NSCLC. As the tertiary generation antineoplastic drug, gemcitabine has been widely used and plays an imporant role. However, the response rate of this single-agent treatment is only 20~25% primarily due to drug resistance. The combination of gemcitabine with platinum was proved to the response rate increase to 30~40%. If a biomarker capable of predicting chemotherapy effect can be found, the effective rate of NSCLC will be greatly increased. Unfortunately, there is no effective method to select the chemotherapy regimen. Gemcitabine is an analog of deoxycytidine(dC) and an inhibitor of ribonucleotide reductase. It works by blocking up DNA synthesis before leading to cell apoptosis. Abnormal DNA synthesis and repair usually contribute to tumorigenesis and multidrug resistance. Nucleotide excision repair(NER) is the major mechanism of DNA repair caused by chemotherapeutics. Excision repair cross-complementing-1(ERCC1) is the rate-limiting enzyme of NER and its overexpression can repair DNA which keeps the cell cycle in the G2/M stage and leads to resistance to gemcitabine and cisplatin. As one of the targets, ribonucleotide reductase(RR) is the rate-limiting enzyme of DNA synthesis pathway, and is also the unique enzyme that converts ribonucleic acid into deoxynucleotide. Ribonucleotide reductase is the precursor of RNA synthesis, participating in the process of ribonucleic acid to deoxynucleotide. It is essential to DNA synthesis and repair. RR includes RRM1 and RRM2. RRM2 is a metal-binding site that can carry the contact inhibition zone and control substrate transformation. As the regulatory subunit, RRM1 is a tumor-suppressing gene and the target of gemcitabine. It can control the substrate specificity and activity of holoenzyme, it playing a very important role. There is currently less research on the relationship between ERCC1, RRM1 and chemotherapeutic effect in NSCLC. Most of the research is based on laboratory studying. Empirical methods can hardly be applied extensively. Therefore, there is no effective method to help us to select a chemotherapy regimen.【Objective】To detect ERCC1,RRM1 expression of the protein level, explore the correlation between ERCC1, RRM1 expression and gemcitabine /cisplatin resistance, and discuss the relationship between the expression of ERCC1, RRM1 and gemcitabine/cisplatin chemotherapy sensitivity and prognosis in NSCLC so as to discuss the potentiality of ERCC1, RRM1 being used as latent prognosis factor for chemotherapy based on gemcitabine.【Method】Seventy-one stageⅢB andⅣNSCLC patients were enrolled in the study. Immunohistochemistry was performed in paraffin-embedded tumor specimens to investigate ERCC1,RRM1 expression. Cox regression analysis was used to screen independent prognostic risk factors for survival. Comparisons of median overall survival and median progression free survival among the different expression of ERCC1,RRM1 groups were based on Kaplan-Merier analysis. To analyze the correlation between ERCC1, RRM1 expression and gender, age, type of histology and clinical stage, and analyze the relationship of ERCC1, RRM1 expression and gemcitabine/cisplatin chemotherapy sensitivity and prognosis so as to explore the feasibility of ERCC1, RRM1 being used as a marker of gemcitabine/cisplatin therapeutic effect.【Results】ERCC1,RRM1 expression was investigated in NSCLC paraffin-embedded tumor tissue by immunohistochemical SP method.The chromaticity-positive cells of ERCC1 were expressed with brown nucleus, ERCC1 (-) or low expression positive cells <10%, ERCC1(+) or high expression with positive cells≥10 %. The chromaticity-positive cells of RRM1 were expressed with brown cytoplasm, RRM1 (-) or low expression with positive cells <50%,RRM1(+) or high expression with positive cells≥50 %. The positive rate of ERCC1 was 46.5% in NSCLC and that of RRM1 was 56.3%. There was no correlation between ERCC1 and RRM1 expression and gender, age, histological type, clinical stage. They were positively correlated. The expression of ERCC1 and RRM1 was associated with clinical effect: patients with negative expression of ERCC1 had better effects than those positive, the difference was statistically significant (P=0.036), patients with negative expression of RRM1 had better effects than that of positive ones, the difference was statistically significant (P=0.003). The survival time of the patients with ERCC1 and RRM1 negative expression was significantly longer than that of positive ones(P=0.002, P=0.001).【Conclusion】Some useful conclusions have been drawn from the research:To detect the expression of ERCC1 and RRM1 in tumorous tissues of NSCLC,the conclusion can be drawn that there is some correlation between the expressions and histological type. The expression of ERCC1 is correlated to that of RRM1. The immunohistochemical method can facilitate the clinical detection of ERCC1 and RRM1 expression. It is expected to be a latent prognosis factor for chemotherapy based on gemcitabine. However, studies of more clinical cases are needed.