Study On The Relationship Between ERCC1, P53 Expression And Sensitivity Of Patient With Advanced NSCLC To Chemotherapy With Platinum Involved

Morbidity and mortality of lung cancer occupied the first place of malignant tumors in our country, with 80% of nonsmall-cell lung cancer (NSCLC) in lung cancer. Unfortunately 65-70% of NSCLC was already in advanced stage when be diagnosed. Therefore chemotherapy plays a vital role in the combined therapy of stage III/IV NSCLC. Since 1980s, accompanying the pharmaprojects and utilization of the third generation agents, such as vinorelbine, gemcitabine, and Japanese yew branchlet, the third generation combined chemotherapy based on platinum became the standard chemotherapy profile. However, the reaction rate (RR) and meso-survive time of chemotherapy remained unsatisfactory. Because of the genetic heterogeneity, even the NSCLC patients with the same kind of pathological phenotype and stage can behave much differently to the same chemotherapy. Hence the tailor chemotherapy (TC) was presented in the 2004 American Society of Clinical Oncology (ASCO), and was prevailed. TC means to take out the most optimal chemotherapy agents based on its genetic characteristics, in order to improve the chemical sensitivity, improve the RR and MST, and to decrease the side effects. According to the conditions, there are seldom studies on the chemosensitivity of extracorporeal tumor cells. There would be much different between the extracorporeal and corporeal chemosensitivity. DNA damage-repair system is the molecular basis for the body to resist the damage, which is important to maintain the stabilization and integrity of the gene groups. Radiotherapy or chemotherapy would induce the damage to DNA, which would consequently weaken the therapeutic efficacy. Molecular markers which can hint the chemosensitivity and prognosis seem to play important roles in TC profiles. P53 and ERCC1 gene are two genes with tight relationship to chemoresistance of lung cancer. To detect the p53 and ERCC1 genes of NSCLC tissues before the chemotherapy can individualize the chemical agents, to be more scientific and rational. This study was approved by the patients and the medical ethics committee. In this study, ERCC1 and p53 protein expressions, pre-operational p53 antigbody of the carcinoma tissue and peripheral blood lymphocyte (PBL) in 49 patients with NSCLC were detected, and the correlation of ERCC1 and p53 expressions were confirmed between those in the NSCLC tissue and in PBL. ERCC1 and p53 expressions of PBL in 74 patients with NSCLC were detected, to evaluate the relationship between the ERCC1, p53 expressions and chemosensitivity to project with TP, NP or GP. Correlation between the hyper-expressions of ERCC1, p53 and chemoresistance to platinum in NSCLC was confirmed. This study can provide a reference for the choice of TC agents, to improve the chemosensitivity, MST and RR.Objects1. To detect the impression of p53, ERCC1 in the carcinoma tissue, peri-carcinoma tissue and PBL of NSCLC patients, to study the correlations of p53 and ERCC1 expressions between carcinoma tissue and PBL.2. To study the relationship between p53, ERCC1 expression of PBL in NSCLC and the SC project with platinum.3. To study the correlation of the p53 expression between in peri-carcinoma tissues and in serum.Methods1. Expressions of p53 and ERCC1 in peri-carcinoma tissues in NSCLC and their clinical values: To detect the expressions of p53 and ERCC1 protein in peri-carcinoma tissues and PBL in NSCLC with immonofluorescence chemistry, and to evaluate their relationship with pathological characteristics, to provide a clinical pathological basis for the TC profiles.2. Relationship between p53, ERCC1 expression of PBL in NSCLC and the SC project with platinum: To dye the p53 and ERCC1 protein in the NSCLC with immunofluorescence cytochemical staining. After 2-4 courses of SC chemotherapy based on platinum, the total overall survival (OS), time to progression (TTP) chemical efficacy and one-year survival of the patients were evaluated.3. Correlation between the p53 antibody, p53 expression and the chemosensitivity of NSCLC: To detect the expression of ERCC1 and p53 protein in peri-carcinoma tissue of NSCLC with immunofluorescence chemistry, to detect the serum p53 antibody concentration, and to perform the SC chemotherapy based on platinum, so as to estimate the near future efficacy.Results1. p53 and ERCC1 expression in the peri-carcinoma tissues of NSCLC and their clinical values: p53 and ERCC1 were mostly nuclear-dyed. They homogeneously distributed in the nuclei, and also plasmatically distributed along the nuclear membrane.2. p53 positive rate of carcinoma tissue, peri-carcinoma tissue, normal lung tissue, PBL of NSCLC, normal PBL were respectively 63.26%,30.61%,8.186,59.18% and 5%. ERCC1 positive rates were 55.10%,26.53%,10.2%,51.10%和10%. P53 and ERCC1 expressions of carcinoma tissue and PBL in NSCLC significantly higher that those of peri-carcinoma tissue, normal lung tissue and normal PBL (P<0.01). the p53 and ERCC1 expressions in the peri-carcinoma tissue and PBL correlated with the clinical stages and lymphonode metastasis (p<0.05).3. p53 and ERCC1 expressions in peri-carcinoma tissue of NSCLC correlated with those in PBL (x2=14.8596 p<0.01;x2=21.291, p<0.01).4. Relationship between ERCC1, p53 expressions and the chemosensitivity of III/IV stage NSCLC to chemotherapy based on platinum: NSCLC patients were divided into 4 groups based on the ERCC1 and p53 positive immunoinfluence markers: EP group (both ERCC1 and p53 highly-expressed) 37 cases; N group (both ERCC1 and p53 lowly-expressed) 29 cases; E group (only ERCC1 highly-expressed) 4 cases; P group (only p53 highly-expressed). The OS in the 4 groups were respectively (months) 10.65±4.91,14.17±6.63,11±7.5 and 11.5±5.75. The TTP in the 4 groups were respectively (months) 7.78±4.59,12.41±7.16,8.25±7.75,10.75±6.12. Both OS and TPP were statistically significant among the groups (P<0.05). OS and TPP in N group were significantly different against the other 3 groups (P<0.01), and no significant difference between the other 3 groups (P>0.05). post-chemotherapy RR in N group was 65.52%, significantly increased against that of EP group (35.13% increase), and there were no significant difference among the other 3 groups (P>0.05). This hints those NSCLC patients with low ERCC1 and p53 expressions can benefit more from the chemotherapy based on platinum.5. Positive expressions of p53 protein in carcinoma tissue with well, moderate and poor differentiation NSCLC were respectively 37.50%,53.84% and 90.00%. p53 positive expression correlated with the tumor differentiation (P=0.04). p53 antibody in NSCLC serum with well, moderate and poor differentiation were 43.75%,30.77% and 75.00%. Serum p53 antibody correlated with the tumor differentiation (P=0.03). In 49 cases, 20 cases were both positive of p53 in NSCLC carcinoma tissue and serum, 12 cases were both negative. 2 cases were positive in carcinoma tissue and negative in serum, 5 cases were negative in carcinoma tissue and positive in serum. There is correlation between the carcinoma tissue p53 protein and the serum p53 antibody (χ2=4.446).Conclusions1. p53 and ERCC1 expressions in NSCLC tissue correlate with the tumor differentiation stage, TNM stage and lymphonode metastasis.2. p53 and ERCC1 expressions in PBL of NSCLC can reflect the p53 and ERCC1 expressions in NSCLC tissue.3. p53 and ERCC1 expressions in PBL correlated with the chemosensitivity based on platinum.4. p53 and ERCC1 expressions in PBL can be used as markers for chemosensitivity and prognosis based on platinum. NSCLC patients with low expressions of p53 and ERCC1 are most suitable for the TC project with platinum.5. Positive expressions of p53 protein in carcinoma tissue or serum p53 antibody hint a low tumor differentiation stage and high malignance.6. Combine test of the carcinoma tissue p53 protein and the serum p53 antibody can be valuable for the diagnose and prognosis of the NSCLC.