| Background and Objectives:Pancreatic carcinoma is one of the common malignant tumors in digestive system. Recent years,the incidence of this malignancy is trend to upgrade obviously. Pancreatic cancer is the fourthleading cause of adult death from cancer in the western industrial developed countries. Due topopulation aging, life style, drinking custom and environment pollution, more and more peoplein our country are suffering from this disease. The routine treatments for cancer are surgicaloperation, radiotherapy and chemotherapy. A number of pancreatic adenocarcinoma patientshave developed into regional invasion and metastasis before diagnosis, because the disease isdelitescent, highly aggressive and highly progressive. However, a great propotion of patientsdiagnosed early and treated with operation die of malignancy recurrent, because of incompleteexcision or early micrometastasis. In 2007, about 37,170 people suffere from this disease, Thefatality number is nearly equivariant with the incidence number (33, 370), that is to say, mostpancreatic adenocarcinoma patients diagnosed would die within one year. At present, thetreatment for the advanced patients is chemotherapy. As a method of systemic therapy,considered with the toxicant side effect, the quality of patients' life, the patients' life span, theeffect of chemotherapy is disappointed. Due to the high incidence and the high mortality rate ofthis disease, it is urgent to investigate novel and effective ways for pancreatic adenocarcinomatherapy.A great deal of experiments including preclinical (animal model or cell level) and clinicalstudies have showed the direct inhibition of cell proliferation, immunomodulation andantiangiogenesis anticancer effects of IFNγin variety of carcinomas. But its clinical applicationis limited because of the short half-time (only minutes), the repeating high dose of vein injectionof the recombinant protein may recur serious systemic side effects.Biotherapy includes gene therapy and immunotherapy. It is based on "alter the hostbiologic reaction with tumor cells to get the antitumoral effects". Assisting with the rapidprogress development tendency of modern molecular biology and immunology, it has beenrecognized as the fourth mode for the cancer treatment followed with surgical operation,chemotherapy, radiotherapy. Biotherapy has got more and more important status in themultimodality therapy of malignance.In this study, we constructed a recombinant adenovirus as gene therapy vectors. The target gene was transfered into the host cells by adenovirus infection. And the host cells'proteinexpression system was utilized to synthesize and secrete therapeutic IFNγprotein. Comparedwith traditional intravenous injection of recombinant protein, intra-tumor injection of Ad-IFNγmay avoid the drawbacks, such as short half-time, required frequent and repeat injection, serioussystem side effects, thus get more obvious anticancer effects. Besides exploring the anticancermechanism of Ad-IFNγin the pancreatic adenocarcinoma, we also studied Ad-IFNγcombinedwith conventional chemical drug gemcitabine, to test whether the combination generates evenmore powerful effect on tumor inhibition.Results:The human pancreatic tumor cell line Capan-2 infected by Ad-IFNγcan expressefficaciously bioactive target protein, both in vitro and in vivo assays indicated it may obviouslyinhibited the tumor cell growth. Both the flow cytometric quantification and and tumor sectionindicated that the IFNγsignificantly inhibited tumor cell growth via cell apoptosis inducing. Invivo, the intratumoral injected Ad-IFNγcould express IFNγIn a durable and stable way, RT-PCRassay revealed the IFNγcould constantly expressed IFNγmRNA for more then seven days;ELISA assay examination results showed the distribution of IFNγwas dominantly focus in tumortissue, then in the blood and liver. During the treatment, no obvious toxicity was observed. Themice treated with Ad-IFNγresulted in potent tumor growth inhibition and decreased the tumorvolume. The inhibition rates were 42.56%±8.50% when compared with PBS group,47.80%±8.96% when compared with Ad-lacZ. The treatment also revealed it increased morenecrosis, decreased the staining of Ki-67 and induced apoptosis in tumor tissues. These resultssuggested that in a human xenograft model, the co-administration of gemcitabine and Ad-IFNγresulted in potent tumor growth inhibition. Statistical differences were observed with respect tothe growth of tumors receiving only Ad-IFNγor gemcitabine.Conclusions:Intratumor injected Ad-IFNγcould be therapeutically applicable for clinical utilization.This method could inhibit pancreatic cells Capan-2 proliferation, induce the cell apoptosis. Theco-administration of gemcitabine and Ad-IFNγresulted in more potent tumor growth inhibition.They may constitute a useful step towards a better clinical treatment of patients suffering frompancreatic cancer. |
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