The Studies Of Recombinant Adenovirus-mediated HSV-TK/GCV Suicide-gene Therapy Controlled By HTERT Promoter Combined Radiotherapy In Animal Models Of Human Pancreas Cancer

Objective:(1) To make the model of human pancreas cancer xenografts in nude mouse.(2) To approach the treatment efficiency of replication defective adenovirus carrying HSV/TK gene under control of the Human Telomerase Reverse Transcriptase(hTERT) promoter and gancyclovir(GCV) combined radiotherapy in nude mouse xenografts model of pancreas cancer.Methods: we made the model of human pancreas cancer (pancreas cancer cell line patu 8988) xenografts in BALB/C nude mouse followed by peritoneal injection of GCV and Ad-hTERTp-HSV/TK by tail vein injection ,bestowed with x-ray 20GY sequently. The antitumor efficacy was evaluated by tumor volume, relative tumor volume, tumor weight, relative tumor prolife relative rate, and tumor growth curve;Tumor tisse HE,PCNA,MVD and FCM also had been applicated.Results: In the presence of GCV, Ad-hTERT-TK combined radiotherapy effectively inhibited growth of human pancreas cancer in a dose-dependent fashion. Ad-hTERT-TK at a dose of 0.6×109 pfu viral particles in the presence of GCV lead to 86.56% inhibition of tumor growth. Ad-hTERT-TK/GCV or radiotherapy alone caused certain inhibition of tumor growth, which were statistically significant as compared to the control group (p<0.01); The inhibition of Ad-hTERT-HSV-tk/GCV combined radiotherapy group compared to Ad-hTERT-TK/GCV group or radiotherapy group also has statistical significance(p<0.05); The detective result of HE,PCNA,MVD,TNUEL and FCM of transplanted tumor tissue confirmed obvious tumor inhibition by Ad-hTERT-TK combined radiotherapy.Conclusion: Obvious tumor inhibition and prolongation of mice survival time was observed in pancreas cancer xenografts in vivo. This system made no damage or loss to normal tissue. The detective result of HE,PCNA,MVD,TNUEL and FCM of transplanted tumor tissue obviously confirmed tumor inhibition by Ad-hTERT-TK combined radiotherapy.All of above indicated: the system of Ad-hTERT-HSV-tk/GCV combined radiotherapy was safe, effective and selective. The resules presented are encouraging to offer a further clinical evaluation of the potential therapeutic benefits of this strategy.