| Stomach carcinoma is found frequently in the progress, the rates ofrecurrence and metastasis after operation are more higher, It often can’tremove off all cancer cells in the body by simply expanding the operationextent, and usually leaves behind vestigial sub-clinical lesions, while gastriccancer is relatively sensitive to chemotherapy, so it’s the main treatmentmethod in advanced gastric cancer (AGC). Assembling analysis suggests thatthe adjuvant chemotherapy used after the radical resection of gastric cancercan improve the cure rate and reduce the risk of recurrence. But the multi-drugresistance (MDR) of chemotherapy in gastric cancer and immunity relativitymay be an important reason for the failure of cancer chemotherapy. If theeffective drugs for patients could be selected before receiving chemotherapy, itwould take important significance for improving the treatment effect.Fluorouracil as the representative of the antimetabolite drugs is the basic drugin the treatment of gastric cancer, the differences in drug metabolism levelhave important influence on drug efficacy. Datas show that the efficiency of5-Fu alonely treating gastrointestinal cancer was only in10%~30%, and thedifferences are very obvious in different patients, Therefore it’s vital to guidethe clinical rationally applying drugs by exploring predictors of the sensitivityto5-Fu chemotherapye. Thymidylate synthase (TS) is an important targetenzyme of chemotherapeutic drugs such as5-Fu and methotrexate and so on,and a key enzyme to affect the fluorouracil effect, the high activity may resultin the drug resistance. By thymidine phosphorylase (TP) must5-Fu iscatalyzed into FdUMP in body, and FdUMP combined with TS and5,10-methylene tetrahydrofolate can form irreversible triple complex and restrainTS, and hinder the synthesis from the beginning of the deoxidationthymidylate (dTMP) and the copy of DNA, only in this way can it exert cytotoxic effects. ABCG2as a new member of ABC super-family ofmembrane transporter protein possesses the physiological functions such asinhibiting the digestive canal to absorb certain xenobiotics and participating inthe formation of the placental barrier and so on, and a new discharge pump ofdrugs related closely to tumor multi-drug resistance, and a common molecularmarker as studying tumor stem cells’s resistance, and gradually becomes oneof the targets in the clinical tumor chemotherapy. The differences amongABCG2gene polymorphism with its expression and function are importantfactors affecting drug resistance and drug individual differences, it can providetheoretical and practical basis for clinical rational drug use, so the detection ofABCG2is benefical to the clinical selection of chemotherapy drugs and forformulating reasonable treatment. Nearly10years the research about thephysiological function of ABCG2transport protein, transport mechanism,clinical drug resistance mechanism and the reversal of drug resistance hasmade some progresses, however still need to be further. But at present theresearch on the relationships among the expression status of ABCG2in gastriccarcinoma, gastric cancer pathological stage, tumor size, with differentiationstatus and so on is rare. The purpose of this study is to detect the expression ofthose two kinds of index (one is5-Fu type drug metabolism enzymes, one is amulti-drug resistance protein) in patients with advanced gastric carcinoma,and analyze its relationship with clinical pathological characteristics, andevaluate its clinical value, so as to predict5-Fu class drug’s effect and thepossibility of ABCG2as a new molecular marker of gastric cancer’s diagnosisand chemotherapy effect, which has the important meaning to improve theefficacy of chemotherapy in gastric cancer and guide individualized treatmentin controlling cancer, so as to promote the drug sensitivity and prolong thesurvival period.Objective:By detecting the expressions of TS (thymidylate synthase) and ABCG2(ATP-binding cassette super-family G member2) protein in advanced gastric cancer (GC) and adjacent normal non-cancerous tissues, to discuss whetherthey are correlated with the clinic-pathological parameters of GC and thepossibility of TS predicting gastric cancer’s clinical stage and metastasis, andABCG2becoming a new molecular marker, and explore the degree ofcorrelation between TS and ABCG2on the predicting gastric cancer’schemotherapy effect and the drug-resistance, so that evidence can be suppliedfor judging the chemotherapy effect of gastric cancer and working out the bestchemotherapy program, and improving the drug sensitivity, and prolonging thesurvival date.Methods:Collecting80cases stomach carcinoma tissues in the advanced period bysurgical excision and pathological diagnosis paired with80cases adjacentnormal non-cancerous tissues with pathology wax blocks. By applyingimmunohistochemistry Envision two-step detecting the expression of TS andABCG2protein in advanced gastric cancer, analysed statistically thecorrelation among them with clinic-pathological differentiation status, TNMstage, tumor size, lymph node metastasis, distant metastasis, P-glycoprotein(P-gp) and so on. The method of Chi-square test and Kruskal-Wallis H testwas mainly applied.Results:Ts and ABCG2were both highly expressed in paired GC tissues withadjacent normal non-cancerous tissues, and TS positive stain was located innucleus and cytoplasm, while ABCG2mainly in cytomembrane, also could bein cytoplasm; Their total positive expression rates in GC were85.0%(68/80),90.0%(72/80), which was significantly higher than that in the adjacent normalnon-cancers tissues of62.5%(50/80) and78.7%(63/80), and the difference wasstatistically significant(χ~2=11.466\16.463, P=0.009,0.001), and the strongpositive rate respectively was21.3%(17/80)and32.5%(26/80); In protein levelthe expression of TS and ABCG2protein in advanced gastric cancer tissuewere both closely related to TNM stage, differentiation status, invasion depthand P-gp(P-glycoprotein)(each P<0.001), but neither with the age, gender, tumor size, or the presence of lymph node metastasis and distantmetastasis(each P>0.05); While the later the tumor stage was the higher theexpression level of TS and ABCG2was, and at the aspect of differentiationdegree and invasion depth, also was the differentiation degree was lower, theinvasion was deeper. But the expression coherence among P-gp respectivelywith TS and ABCG2in gastric cancer was poor(Kappa=0.004,0.126), and nostatistical significance(P=0.072,0.075); TS and ABCG2had a positivecorrelation(r=0.076), but this was not statistically significant(P=0.342),however on the expression strength their coherence was poor(Kappa=0.135),though there was statistical significance(P=0.026).Conclusions:TS and ABCG2in advanced gastric cancer tissue have excessiveexpression, their positive expression rate is significantly higher than normaltissue, can be as sensitive indicator in the detection of gastric cancer, they areboth closely related to tumor differentiation status, stage, and invasion, as thelater the tumor stage is, the lower the tumor differentiation degree is, thedeeper the tumor invasion is, the higher the positive expression rate is. Theyare also related to P-gp, indicating that TS and ABCG2are connected withdrug-resistance of gastric carcinoma, but there is no coherence among TS andABCG2with P-gp in the expression level of gastric cancer, joint detectionmaybe enhance the diagnosis of the resistance in gastric carcinoma, TS andABCG2might serve as a novel predictor of malignancy, tumor progression, aswell as drug-resistance or not and the prognosis in gastric cancer, thoughABCG2is more expected to become the new target of the diagnosis andcurative effect of stomach cancer. |
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