Experimental Studies On Therapy For Hepatocellular Carcinoma With Gene-viral Therapeutic Systems Carrying Mouse Endostatin

Experimental Studies on Therapy for Hepatocellular Carcinoma with Gene-viral Therapeutic Systems Carrying Mouse EndostatinBackground and objectives Heptocellular carcinoma (HCC) is one of the most common cancers with a poor survival rate. Novel therapeutic strategies are urgently needed for HCC since advances in conventional therapies have not yet improved the prognosis significantly The only curative options for HCC are surgical resection or liver transplantation, which are only indicated for a minority of patients. Furthermore, recurrence rates for those undergoing resection approaches 70%. Palliative treatment options such as chemotherapy, immunotherapy, radiotherapy, or even conventional gene therapy are rarely beneficial. Novel therapeutics is urgently needed for HCC. For half a century, the idea of using replication-competent viruses to treat human cancer has been revisited with various investigators. However, only recently has our understanding of viral and cancer biology progressed to a stage where tumor-specific replication-competent viruses could be engineered. Generally, three broad strategies are currently being used to achieve tumor-specific replication-competent viruses. One approach is to target virus infection at tumor cells by exploiting cell surface aberration that is characteristic of malignancy. An alternative approach is to restrict the replication of virus in tumor cells by taking advantage of intracellular aberration in gene expression which is the basis of malignancy. The third approach is to link virus replication to the transcription of cellular genes that are expressed in a tumor-specific manner. In theory, these recombinant viruses are able to replicate selectively in and lyse tumor cells while leaving the immediately adjacent normal cells unaffected, giving them another name as oncolytic viruse. This appealing property offers promises for cancer gene therapy and several studies on replication-competent viruses have entered clinical trials. Nevertheless, the tremendous promise of studies in preclinical models has not yet been translated into similar patient benefits in clinical setting. As a successful paradigm of oncolytic virus, ONYX-015 (dl1520), an E1B 55kDa-deficient adenovirus, showed encouraging experimental results both in vitro and in vivo. However, the outcomes of clinical trials using ONYX-015 as monotherapy have been disappointing, revealing that the antitumor efficiency of this oncolytic virus as a single agent is somehow limited.The efficiency with which viruses transfer their genes from one host cell to another has led to the widespread use of viruses as vectors in gene therapy. However, for safety reasons, virus vectors employed in conventional cancer gene therapy are generally replication-deficient viruses, limiting the efficacy of gene transfer by restricting the number of tumor cells to which the therapeutic gene is delivered. To solve this problem, tumor-specific replication-competent viruses have been proposed as vectors. These viruses themselves are capable of lysing tumor cells selectively, and more importantly, their selective replications will amplify not only themselves but also the carried therapeutic genes in tumor cells. The marriage of oncolytic virus with therapeutic gene is expected to create synergism that would surpass either of them alone and this speculation was validated with outcomes of experiments on the oncolytic viruses coupling to transgene therapy.Angiogenesis is involved in tumor growth as well as metastasis.Targeting antiangiogensis with angiogenesis inhibitors was proved to be an effective strategy in antitumor gene therapy. During the last few years more than 20 potent endogenous angiogenesis inhibitors were discovered and among the angiogenesis inhibitors described so far, the recently discovered protein endostatin is the most potent one. Theoretically, armed with a therapeutic gene like murine endostatin, oncolytic viruses may have their antitumor potency augmented. The E1B 55kDa gene is essential for the replication of...