The Relationship Of Drug Resistance Associated Protein, Mismatch Repair Protein Expression To Drug Resistance In Gastrointestinal Carcinoma

Background & objectives: Gastrointestinal carcinoma is one of the most common malignanttumors. And chemotherapy is the necessary adjuvant way ofgastrointestinal carcinoma treatment. However drug resistance in the canceroften leads chemotherapy to fail. Many researchers are trying to find theways to resist and reverse drug resistance of cancer cells many years, butthey do not get satisfied answers yet. It is mainly because that themechanism of drug resistance is still unclear. Now people have known thatdrug resistance in the cancer is a complex progress, involving changes ofmany proteins expression including drug resistance associated proteins,oncogene proteins, tumor suppressor genes proteins, cell cycle proteins,apoptotic proteins, mismatch repair proteins, et al. Drug resistanceassociated proteins are regularly thought to have close relationship to theoccurrence of drug resistance, which includes many proteins, such asmultidrug resistance associated protein (P-gp), lung resistance protein(LRP), glutathione-S-transferase pi (GST-pi) and Topoâ…¡. They take part indrug resistance by decreasing the concentration or toxicity of drug in cellsand changing the target of drug. Mismatch repair (MMR) systems canmaintain the fidelity and stability in the process of DNA synthesis. It wasreported that missing of mismatch repair functions might lead tomicrosatellite instability and collection of some gene mutations. Recently,MMR proteins were noticed to play a role in drug resistance. Some peoplefound that missing of MMR function was associated with drug resistance incancer cells from platinum and anti-metabolizing. In this study we detectedthe sensitivity to 5 common anti-cancer drugs, and protein expressions ofLRP, GST-pi, hMSH2 and hMLH1 in extruded gastrointestinal carcinomatissues, gastric carcinoma cell line BGC823 and its resistance cell lineBGC823/cDDP, in order to explore the mechanism of drug resistance incancer cells. Methods: (1) In 23 gastrointestinal carcinoma tissues, MTT assay was used totest sensitivity to five anti-cancer drugs of cisplatin, carboplatin,5-fluorouracil, vincristine and mitomycin; immunohistochemistry was usedto detect protein expression of LRP, GST-pi, hMSH2 and hMLH1;statistical assay was used to analysis the relationship of drug sensitivity toprotein expressions. (2) Cell culture and gradually increasing does ofcisplatin and intermittent administration was used to establish cisplatinresistance cell line BGC823/cDDP; MTT assay was used to test sensitivityof gastric carcinoma cell line BGC823 and its resistance cell lineBGC823/cDDP to cisplatin, 5-fluorouracil and vincristine,immunocytochemistry was used to detect protein expression of LRP,GST-pi, hMSH2 and hMLH1 in these two cell lines. Results: (1) The positive rate of LRP in carcinoma group and in surroundinggroup or GST-pi were 74%, 65% or 73%, 59%, respectively, and there wasno significant difference of either protein positive rate between the twogroups. Any protein expression in carcinoma tissues was significantlycorrelated with that in its surrounding tissues (p<0.05), but LRP andGST-pi expression in carcinomas had no relationship with each other.Positive rate of hMLH1 (57%) in carcinoma group was significantly higherthan that (23%) in surrounding group (p<0.05). Positive rate of hMSH2was no significant difference between carcinomas (74%) and itssurrounding tissues (59%) (p<0.05). hMLH1 and hMSH2 expressions incarcinomas had no relationship with each other. Drug resistance associatedprotein LRP, GST-pi and mismatch repair protein hMLH1, hMSH2expression in carcinoma tissues had no relationship with each other, too. (2)To carboplatin, positive rate of GST-pi in middle resistance group (100%)was significantly higher than that in non-resistance group (50%)(p<0.05).While to other four anti-cancer drugs, there was no significant differencebetween groups with different sensitivity of carcinomas. To any proteinpositive rate of LRP, hMLH1, hMSH2, there was no significant differencebetween groups with different sensitivity of carcinomas to any anti...