An evaluation of the efficacy of adenovirus-mediated gene therapy with p53 for the treatment of cancer

Abstract

Cancer is the second leading cause of mortality in the United States today, and equally prevalent throughout the world. Traditional treatments such as chemotherapy and radiotherapy have thus far proven unable to treat the disease with high efficacy, with different cancer types often requiring different treatments providing a spectrum of results. Cancer types in the late stages often have no adequate treatment at all. Over the past two decades, research in the field of gene therapy has created new hope in finding a remedy for cancer that displays a high efficacy in treating many different types and stages. The p53 tumor suppressor gene has garnered a great deal of interest, as p53 mutation or inactivation is present in approximately 50% of all cancers. The loss of p53 activity can be attributed to several different causes, including mutation of the p53 gene or overexpression of p53 inhibitors. Research has illustrated that the p53 protein plays an important role in tumor suppression by inducing senescence, cell cycle arrest, or cell apoptosis. Studies have shown that reactivation of p53 in tumor cells leads to tumor cell apoptosis and overall tumor regression. The focus of p53 research has now shifted to strategies of reintroducing or reactivating the gene in tumor cells so that it may carry out its anti-tumor functions. Of the strategies proposed, the use of adenovirus to introduce p53 shows the most promise. Adenoviruses bind to and enter the cell, and, after escaping proteasomal degradation, travel to the nucleus where they inject their genetic material. By delivering wild-type p53 gene into tumor cells using adenovirus, large amounts of p53 protein are transcribed in the cell and initiate its antitumor properties. Many clinical trials using adenovirus-mediated p53 gene transfer (Ad-p53) have been performed with generally positive results across a variety of cancer types. Ad-p53 in combination with more traditional treatments like chemotherapy and radiotherapy has been especially promising. The engineering of both adenoviral vectors and the p53 gene to be delivered presents new options for further increasing the efficacy of this therapeutic approach. Both Onyx-015, a selectively replicating adenovirus, and Ad-p53vp, a p53 gene that avoids inhibition, have been used in clinical trials with success. As a whole the field of adenovirus-mediate p53 gene transfer is promising and holds many advantages to classical treatments, but is still in the early stages of research. Further research must be completed so this therapy may be widely approved and used. The specific combination of Ad-p53 and traditional therapies has proven highly effective and should be used in clinical settings immediately.