| Virus mediated tumor targeting is one of the newly appeared promising biotherapy of malignant tumor. Adenovirus is one of the mostly studied projects, because it possesses several attributes that are favorable for their development as anti-cancer agent. Adenoviruses have a favorable safety profile because of their low pathogenicity, their non-integrating genome and their genetic stability. Also, manufacturing and handling of adenoviruses as drugs benefits from the ease of virus production at high tilers and the high stability of adenovirus particles. Additionally, adenovirus has wild infection in normal population and had long application history, thus utility of adenovirus had been ensure its safety.Since the E1B-55kD gene product is responsible for P53-binding and inactivation, it was hypothesized that the deletion mutant would be unable to inactivate P53 in normal cells and would thus be unable to replicate efficiently. In contrast, cancer cells lacking functional P53 would be expected to be sensitive to viral replication and subsequent cytolysis. However P53 defections wildly exist in most of human cancer cell, deletionof E1B-55kD gene can make the adenovirus target at p53 mutation tumor cell. Moreover an E3 region deletion may activate the host to adenovirus infection tumor cell immunity so as to enhance the treatment efficacy. Because the production of E3 region gene encode several protein to help adenovirus to evade immune response, for instant, gp19KD protein can inhibit type I MHC Ag express to the cell surface and 10. 4/14. 5KD, 14. 7KDprotein can inhibit FasL or TNFa mediated cytostatic effect.However the safety effectiveness and clinical feasibility of recombinant adenovirus should be further studied at clinical trial before its application to treat human cancer. In vitro and animal study had proved that the E1B deleted recombinant adenovirus had tumor cell target effect and a sound tumor mass inhibition. Toxicology of animal mode did not show immediate and long toxicity or allergy reaction due to E1B deletion recombinant adenovirus. Consequently E1B deletion adenovirus had been approved to take clinical trial by China State Food and Drugs Administration. We had observed the short term human safety and environment safety by intra~tumor injection of E1B deleted adenovirus, when it is proved to be safe to human body we observed its efficacy in combination with chemotherapy to different tumor.The result obtained through the clinical trial show that E1B deleted adenovirus had relatively high safety and also show potential anticancer activity in some tumor type. And the effect had obvious relationship to immune response. However the therapeutic effect did not strong enough, so further improvement should be studied.Currently strategy to enhance virotherapy effect are: 1. To change the virus structure to enhance its target effect, for example flagellum modification; 2. To apply with certain therapeutic gene to enhance it anticancer effect; 3. study the mechanism of how virus enhance chemotherapy and radiotherapy effect, to decrease the dosage of such treatment, so as to decrease the untoward reaction to patients; 4. To further filtrate strong but still safe virus to recombine for cancer therapy.However combined with immune gene therapy may outline the advantage of virotherapy, because the virus had high infection rate than other vector, especially to replication competent virus, can enhance theexpression of carried gene in multiple fold. And with tumor specific gene promoter can enhance the target effect of virus mediated tumor therapy.Midkine is a kind of heparin bind factor, which play a important role to cell growth and differentiation, but only exist in the kidney after born. Recent research show that Midkine expressed intensely in a wide range of carcinomas in liver cancer, gastric cancer, pancreatic cancer, colon cancer, esophagus cancer, ovary cancer, breast cancer, lung cancer, prostate cancer, et al, and correlated with it progression. Midkine expression was elev...
|
PDF Full Text Request