| BackgroundGastric cancer is one of the common malignant tumors in clinic. At present, the treatment effect is quite unsatisfactory , it is very difficult to obtain good effects only depending on surgery, and recurrence rate is very high. So, it is particularly important for post-operative adjuvant therapy .Chemotherapy plays an important role in the treatment of gastric cancer .However, the effect of chemotherapy in post-operative adjuvant therapy in gastric cancer is not satisfactory, the sensitivity of chemotherapeutic drugs is poor, the reason involves tumor cell proliferation,apoptosis,resistance formation,lack of individualized treatment programs and so on. Due to multi-drug resistance and tumor heterogeneity phenomenon, the same types of tumors in different individual and the same individual at different stages of tumor development have different sensitivity to the same drug , in clinical Chemotherapy ,the same chemotherapy drugs or experience chemotherapy have certain defects. With the rapid development of molecular biology techniques, Chikhi gene diagnostic kit and chip for clinical tumor drug therapy will be widely used,doctors can administration according to the genetic data of cancer patients, achieving the purpose of individual chemotherapy. Thus, the key to improve the effects of chemotherapy in gastric cancer is how to choose sensitive anticancer agent and making individual treatment programs.ObjectiveWe select chemotherapy drugs through the application of drug sensitivity test, use chemotherapy drugs treated tumor-bearing mice with Several generations, investigate clinical effects, detect the expression of genes correlated with proliferation,apoptosis,resistance in mice gastric cancer tissue, discuss the choice of chemotherapeutic drugs and analyze if clinical effects and gene expression coincide for implementing scientific and drug adaptation individual programs.Methods and resultsMulti-drug resistance (MDR) is the main reason for the failure of chemotherapy which needed to be solved urgently in tumor chemotherapy. Drug resistance of tumor cells is the main cause for less sensitivity to gastric cancer chemotherapy, patients with advanced gastric cancer treated with traditional chemotherapy have a short paracmasis, this may be related to the rapidly emerging drug resistance.Multi-drug resistance mediated by P-glycoprotein (P-gp) which was encoded by multi-drug resistance gene (MDR1) was researched most, research shows that over-expression of P-gp/MDR1 is the molecular basis of tumors multi-drug resistant. MDR1 can remove the toxic compositions of chemotherapy drugs against its concentration gradient , MDR1 have high expression in tumor tissues, this drug resistance mechanism applies to natural or semi-natural hydrophobicity lipophilic cytotoxic drugs ,including anti-tumor antibiotics such as anthracycline antibiotics, actinomycin D, mitomycin ,anti-tumor Alkali plants and Colchicine etc. Our experiment found that Chemotherapy drug Adriamycin less sensitive to mice gastric cancer cell lines have poor effect for systemic chemotherapy ,low efficiency of inhibiting tumor growth and high MDR1 gene expression, we get similar results when using Adriamycin Chemotherapy on the second generation of tumor-bearing mice for systemic chemotherapy. However, Chemotherapy drug 5-fluorouracil screened through drug sensitivity test sensitive to mice gastric cancer cell lines have good effect for systemic chemotherapy and high efficiency of inhibiting tumor growth, but it,s MDR1 gene expression is also very high, the possible reason is that tumor cells themselves have Primary drug-resistant. After chemotherapy on the first generation of tumor-bearing mice, the tumor cells after 5-fluorouracil chemotherapy screen cisplatin out as the most sensitive chemotherapy drug, the tumor cells after Adriamycin chemotherapy screen mitomycin out as the most unsensitive chemotherapy drug, using cisplatin Chemotherapy on the second generation of tumor-bearing mice , we found that cisplatin group have good effect and high efficiency of inhibiting tumor growth ,however, the MDR1 gene expression compared with the control group, 5-fluorouracil group and Adriamycin group has no significant differences, using mitomycin Chemotherapy on the second generation of tumor-bearing mice , we found that mitomycin group have poor effect and low efficiency of inhibiting tumor growth, the MDR1 gene expression compared with the control group, cisplatin group ,5-fluorouracil group and Adriamycin group was significantly higher, it demonstrates that mitomycin chemotherapy may up-regulat the expression of MDR1.Tumor-bearing mice,s high MDR1 expression after unsensitive drug chemotherapy indicate that it may have acquired drug resistance after Chemotherapy. people with positive MDR1 gene expression selecting antibiotics chemotherapeutic agents such as Adriamycin, mitomycin have poor effects, but the effect of cisplatin is good, this result is conformity to drug sensitivity test, thus people with positive MDR1 gene expression should avoid using natural or semi-natural anticancer drugs, but can choice alkylating agent and anti-metabolism drugs with little relation to P-gp.In the incidence of gastric cancer cell apoptosis plays a specific role , and the development of gastric cancer is closely related to cell apoptosis ,it is the result of an imbalance between cell apoptosis and proliferation. Cell apoptosis is an active cell suicide process regulated by gene, many human genes such as p53, bcl-2 participate in the regulation of apoptosis. The depress rate of tumor cell apoptosis may be associated with P53 gene mutation and it's abnormal protein expression, P53 protein in tumor may be increase 5-10 times compared with the normal. Over expression of bcl-2 specificitily inhibit cell apoptosis in response to a certain stimulus, promote the development of tumor, increase tumor invasion and dissemination, so bcl-2 is also called apoptosis suppressor gene. Research has also found that bcl-2 can express in gastric cancer. Bcl-2 expression has associated with clinical prognosis of multiple tumors, in gastric cancer, if Bcl-2 expression decrease apoptotic index will obviously increase. Inducing cell Apoptosis may be one of the principal mechanisms that chemotherapeutic drugs inhibit tumor growth, chemotherapeutic drugs can regulate gene expression of tumor, regulate gene alteration of cell apoptosis in gastric cancer, induce the development of apoptosis, regulate the rate of proliferation and apoptosis, then attain the purpose of tumor regression. Chemotherapeuic drugs can mediate cell apoptosis through P53, bcl-2 pathway. Through this experiment we can see that through drug sensitivity test we screen out chemotherapy drug 5-fluorouracil which is sensitive to mice gastric cancer cell line, using it for systemic chemotherapy on the first generation of tumor-bearing mice ,it have good effect, high efficiency of inhibiting tumor growth, high rate of tumor cell apoptosis and low expression of bcl-2 and P53 protein. Chemotherapy drug Adriamycin less sensitive to mice gastric cancer cell lines have poor effect for systemic chemotherapy and low efficiency of inhibiting tumor growth, low rate of tumor cell apoptosis and high expression of bcl-2 and P53 protein. However, after chemotherapy on the first generation of tumor-bearing mice, through drug sensitivity test we found that the sensitivity of tumor cells to chemotherapeutic drugs change, the tumor cells after 5-fluorouracil chemotherapy screen cisplatin out as the most sensitive chemotherapy drug, the tumor cells after Adriamycin chemotherapy screen mitomycin out as the most unsensitive chemotherapy drug, using cisplatin Chemotherapy on the second generation of tumor-bearing mice, we found that cisplatin group have good effect, high efficiency of inhibiting tumor growth ,high rate of tumor cell apoptosis and low expression of bcl-2 and P53 protein, using mitomycin Chemotherapy on the second generation of tumor-bearing mice, we found that mitomycin group have poor effect, low efficiency of inhibiting tumor growth, low rate of tumor cell apoptosis and high expression of bcl-2 and P53 protein. So inducing tumor cell apoptosis is the foundation and key to successfully cure cancer, in addition to directly through their respective targets chemotherapy drugs can also kill tumor cells by inducing apoptosis. Through using chemotherapy drug screened through drug sensitivity test treat tumor-bearing mice, the study of apoptosis and P53, bcl-2 gene Expression, Our experiment provids important ideas and methods for the choice of cancer chemotherapy drugs and the prognosis judgement.The growth, invasion and metastasis of tumor is a complicated process affected by many factors, its prerequisite and basis is the continued proliferation of tumor cells, the necessary condition for growth and metastasis of tumor is angiogenesis. Finding the specificity index in the process of tumor invasion and metastasis is helpful for judging prognosis of patients with gastric cancer and taking effective treatment measures, according specific circumstances make individual treatment programs to improve the survival rate of patients with gastric cancer. ErbB-2 is a proto-oncogene, with tyrosine kinase activity , is a epidermal growth factor receptor family member, doesn't express in normal cells, Over express in multiple malignant tumors, the positive rate rangs 10%～60%in various tumor , has an intimate association with prognosis and therapeutic effect and is a sign of worsening cancer. ErbB-2 protein functions include participating cell proliferation, cell differentiation etc. when ErbB-2 gene activate it's structure change ,this can lead to ErbB-2 protein over-expression and stimulate cell proliferation, invasion and metastasis , over-expression often suggest that tumor have strong proliferation ability ,high degree of malignancy and poor prognosis, this has association with metastasis and chemical resistan.. Through drug sensitivity test we screen out chemotherapy drug -fluorouracil which is sensitive to mice gastric cancer cell line, using it for systemic chemotherapy on the first generation of tumor-bearing mice ,it have good effect, high efficiency of inhibiting tumor growth, low expression of erbB-2 and P53 protein. After using Chemotherapy drug Adriamycin less sensitive to mice gastric cancer cell lines Chemotherapy on mice, the expression of erbB-2 and P53 protein compared with the control group has no significant differences. However, after chemotherapy on the first generation of tumor-bearing mice, through drug sensitivity test we found the tumor cells after 5-fluorouracil chemotherapy screen cisplatin out as the most sensitive chemotherapy drug, the tumor cells after Adriamycin chemotherapy screen mitomycin out as the most unsensitive chemotherapy drug, using cisplatin Chemotherapy on the second generation of tumor-bearing mice, we found that cisplatin group have good effect, high efficiency of inhibiting tumor growth and low expression of erbB-2 and P53 protein . using mitomycin .Chemotherapy on the second generation of tumor-bearing mice, we found that mitomycin group have poor effect, low efficiency of inhibiting tumor growth and high expression of erbB-2 and P53 protein. Also using 5-fluorouracil and Adriamycin Chemotherapy on the second generation of tumor-bearing mice , we found that5-fluorouracil andAdriamycin group have poor effect, low efficiency of inhibiting tumor growth and high expression of erbB-2 and P53 protein. From this study we can see that through drug sensitivity test screen chemotherapy drug, guide chemotherapy on gastric cancer in mice , We use chemotherapy drugs sensitive to mice gastric cancer cells for chemotherapy, it has low expression of erbB-2 and P53 protein and good clinical effect, the results is concordant with drug sensitivity test.ConclusionThese results suggest that treating tumor-bearing mice with chemotherapy drugs screened from gastric cancer cells in mice can induce gastric cancer cells apoptosis, inhibit erbB-2, P-53, bcl-2 gene expression, the effect is concordant with drug sensitivity test. Gastric cancer tissue in mice has endogenous MDR1, higher primary resistance and may induce resistance in chemotherapy, this is probably one of the reasons for poor results in gastric cancer chemotherapy. Thus drug sensitivity test before chemotherapy, in addition to drug instruction, may also avoid unnecessary chemotherapy drug toxicity caused by blind employment of non-sensitive chemotherapy drug, finally favors the detection of resistance case. In addition to the tumor chemotherapy drug sensitivity determination, gene expression examination associated with proliferation, apoptosis, drug resistance and metastasis is also suggested. According to the results of gene test, choosing suitable chemotherapy drug can result in a better clinical effect, which is of great importance to improve the rate of tumor treatment, reduce drug toxicities, blindness and the occurrence of resistance. In short, this paper established an animal model of drug sensitivity test, elucidate the importance of cancer chemotherapy, Of course, there are differences between animal and human model, experiments in vitro and in vivo are also different, further, more experiments are needed to explore and discuss in this field.
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