Conditionally Replicative Adenovirus CNHK 500 In The Treatment Of Breast Cancer In Vitro And In Vivo

A variety of gene therapies for cancer have been developed by using replication-deficient virus vector, about 2/3 onging gene therapy clinical trials aims at cancer. The use of recombinant adenoviruse as a vehicle to transfer genes into targeted cells for treating disease has several important advantages, such as safety; non-integrity into human genome; high virus titres and easy purification and produciton, etc. But unfortunately, its high immunogenicity, the deficiency of infecting specificity and poor penetration in tumor tissues affect its clinical efficacy greatly. The last two reasons are just the two major restriction factors that inhibits the progress of gene therapy.To improve virus infecting specificity and penetration capability in tumors, The scientists turned to research and develope new kinds of conditionally-replicating virus vector to deliver cancer therapeutic genes. Replication-competent viruses itself also have been used to treat cancer individually, they have several appealing advantages in treating cancer. Firstly, replication-competent viruses can replicate selectively in the tumors, amplifies the input dose, such reduce the doses needed to achieve efficacy, and the parental virus amplify in tumor cells, then spread and infect the adjacent tumor cells after its releasing from the virus-mediated-lysed cell, while conventional chemotherapy followed the principle of log cell killing kinetics, killing a proportional number of cells with a given dose of drug regardless of the tumor burden; Secondly, viral proteins associated with either tumor cell membrane fragments or intact cells may enhance the immunogenicity of tumor antigens, thereby, augmenting host cellular and humoral-mediated destruction of the tumor; Fruthermore, a very natural extension of virus-mediated gene delivery is the treatment of human tumors with a replication-selective, transgene-expressing virus, which, in theory, offers several potential advantages. The oncolytic virus is itself capable of lysing the infected tumor cell to eradicate or reduce the tumor mass, and more importantly, the virus replication leads to amplification of the imput dose of the virus, and these progeny viruses will infect the surrounding cells ,the majority of progeny virus will express a large amount8of therapeutic genes in the tumor cells, the antitumoral effect will be augmented efficently; Finally, scientists can improve the virus infectivity and specificity by altering the viral fiber protein responsible for the primary virus-cellular receptor binding ; and most importantly, the selectively-replicating virus can amplify mainly in tumor cells, such greatly control the side-effects induced by virus vectors.Two major strategies have been applied to achieve tumor selective replication of virus. One approach is to delete the viral gene essential for replication in normal cells but not in tumor cells, such as the genes responsible for activating the cell cycle through P53 or RB binding. ONYX-015 is an E1B 55KDa deleted adenovirus claimed to replicate selectively in P53-deficient tumor cells and therefore could be used as an oncolytic virus. The alternative approach is to use tissue or tumor specific promoters to control the expression of essential viral genes through binding of tissue or tumor specific transcription factors. Both adenovirus and HSV have been engineered to put the expressing of regulatory genes under the control of tissue or tumor specific promoters.A variety of characteristic promoters for cancer cells had been used to control the expression of genes in tumors, such as Carcinoembryonic Antigen (CEA) for colon-rectal carcinoma, MUC1 for breast cancer, alpha fetoprotein (AFP) for hepatocelluar carcinoma, prostate-specific antigen (PSA) for prostate cancer as well as Epstein-Barr virus promoters for Naso Pharyngeal Carcinoma (NPC). Although the above tissue or cancer specific promoters can help the genetically modified virus to fullfill selectivity of viral replication in targeted cancer cells, their limitations are obvious as well.