Study On Oncolytic Adenoviruses Respectively Armed With CADD45α Or CADD45γ For Cancer Therapy

Nowadays,malignant tumors have become the first-leading lethiferous disease that harm people's health and lives.The morbidity and mortality of tumor patients have increased dramatically each year,.Traditional therapies such as surgery, radiotherapy and chemotherapy were found to no help, tumor recurrent rates and mortality rates remain very high, which indicate that the development of traditional therapies has been trapped. Therefore, it is urgent to find an effective and security methods to cure it.However,with the development of tumor,people present many new ideas and methods to overcome it,and the gene therapy and viroherapy for cancer treatment have well developed. The conditionally replicating adenoviruses (oncolytic adenoviruses) has become the most potential therapy vector that target gene. Prof. Liu then propose a novel strategy for cancer treatment named"Targeting Gene-Virotherapy of Cancer"in 2001. The strategy is to incorporate one or more therapeutic genes into oncolytic viral vector, which has brought new light and hope for cancer treatment.Growth retardation and DNA damage gene(growth arrest and DNA damage, Gadd) called DNA damage inducible transcript 1, DDIT1Gene family has three members called Gadd45α,Gadd45βand Gadd45γ,is the first downstream gene of p53 that be found.Among these,gene Gadd45αcan rapidly produced by a variety of DNA damage factors and growth factors which act on cells by blocking a different pathway.Regulation by p53 and BRCA1,and have an important relationship with maintenance of genome stability,thereby inhibiting the development of malignant tumors. Gadd45βmainly related to the regulation of p53 and JNK,then inhibit cell growth and participate in the process of apoptosis.Play an important role in cell cycle control,DNA repair and signal transduction. Under some stimulation such as ionizing radiation,ultraviolet radiation ,a variety of agents and mutagenic DNA base damage Gadd45γcan be induced to express.It play a negative regulation on cell growth through cell cycle arrest and apoptosis,have the effect of inhibit cell proliferation and cell apoptosis. Gadd45 protein participate in the regulation of genomic stability through a variety of ways,and have closely related with cell survival,apoptosis,transformation and tumor formation.Base on the idea of"Targeting Gene-Virotherapy of Cancer,we combine anticancer gene to oncolytic adenoviruses,make gene therapy and Virotherapy together to target tumor cells.We insert Gadd45αand Gadd45γgene into oncolytic adenoviruse's carriers ZD55 respectively,and to reconstruct virus called ZD55 -Gadd45α,ZD55- Gadd45γ.In vitro experiments show that ZD55 -Gadd45α,ZD55- Gadd45 have killing effect on tumor cells,such as Hepatic carcinoma and colon cancer,but have weak killing for normal cells.Hoechest dyeing experiment shows that ZD55 -Gadd45α,ZD55- Gadd45γcan induced apoptosis.Therefore we use western blot experiments to detect proteins associated with Gadd45α,Gadd45γinduce apoptosis by signaling pathways.Our study can prove oncolytic adenoviruses with gene Gadd45α,Gadd45γhave better effect on killing tumor cells,and provides a reference for cancer treatment.