The Expression Of ERCC1, GST-π And TS In Gastric Cancer And Their Predictive Value For Patients Treated With 5-FU/DDP Adjuvant Chemotherapy

BACKGROUND AND OBJECTIVE:The main effect of cisplatin is an induction of intrastrand and interstrand DNA cross-links.Proteins of the nucleotide excision repair(NER)pathway are believed to repair DNA damage caused by platinum agents.Moreover,the excision repair cross-complementing(ERCC)gene family prevents damage to DNA caused by nucleotide excision and repair.The interactions between the product of the ERCC1 gene and XPA(Xeroderma pigmentosum group A)and XPF are critical in this repair process.Moreover, correlations between increased ERCC1 expression and response and survival have been reported for sevaral solid tumor.Fluoropyrimidines are widely used to treat gastric cancer,and high levels of their target,enzyme thymidylate synthase(TS),have been correlated with drug resistance and a poorer outcome.TS is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides required for DNA synthesis and is also a critical target for fluoropyrimidines.Glutathione and other components of the glutathione metabolic pathway may also have critical roles in determining cellular sensitivity to platinum-based chemotherapy.Glutathione S-transferase pi(GST-π)is a member of a family of isozymes that play an important role in the detoxification of many xenobiotic substances through conjugation to glutathione.GST-πparticipates directly in the detoxification of platinum compounds.In fact,immunohistochemical studies have shown that GST-πexpression may be a predictive maker to cisplatin-based adjuvant chemotherapy.The aim of this study was to determine whether expressions of the ERCC1,TS and GST-πpredict clinical outcome in patients resectable gastric cancer patients treated with 5-FU/cisplatin adjuvant chemotherapy.METHODS:A total of 65 gastric cancer specimens were collected.The expression of ERCC1,TS and GST-πwas investigated by immunohistochemical staining(S-P method)with specific monoclonal antibodies.Statistical analysis was done by SPSS 13.0 and P＜0.05 was considered significant.RESULTS:In the pathological specimens of 65 cases,the positive rates of ERCC1,GST and TS expression in gastric cancer were 33.8%(22/65),63.1%(41/65) and 47.7%(31/65),located in the nucleus,cytoplasm/nucleus and nucleus/cytoplasm respectively.The expression of ERCC1,GST-π,and TS was not correlated with gender,age,PS,pathologic types,the number of lymph node metastasis and depth of invasion.There was no significant difference(P＞0.05).The DFS of ERCC1-positive patients was 12.5 months,significantly lower than that of the negative(15.4 months)(P＜0.05).The survival curve of ERCC1 positive expression was significantly lower than the negative,with median OS 19.7 months(95%CI=17.2 to 22.0)and 23.8 months(21.0 to 26.5)respectively,There was a statistically significant difference between the two(P＜0.05).The DFS of GST-πpositive patients was 13.6 months,significantly lower than that of the negative(14.9 months)(P＜0.05).The survival curve of GST-πpositive expression was slihgtly lower than GST-πnegative,with median OS 21.1 months(95%CI=20.0 to 23.6)and 23.7 months(20.3 to 27.2)respectively.But the differences did not reach statistical significance(P＞0.05). The DFS of TS-positive patients was 13.3 months,significantly lower than the negative(16.9 months)(P＜0.05).The survival curve of TS positive expression was significantly lower than the negative,with median OS 20.1 months(95%CI=19.0 to 21.9)and 25.2 months(22.4 to 28.0)respectively,There was a statistically significant difference(P＜0.05).CONCLUSIONS:The expression of ERCC1 and TS is related with the prognosis of the patients of gastric cancer.ERCC1,TS-negative patients with good prognos is suggested longer DFS and OS.The negative of GST-πexpression has longer DFS.ERCC1 and TS have a certain predictive value for Prognosis of Resectable Gastric Cancer Patients Treated with 5-Fluorouracil and cis-Platinum Adjuvant Chemotherapy.But the impact of GST-πexpression on the prognosis of patients needs to be confirmed with further experiments...