We have developed replication-competent oncolytic adenovirus (Ad) vectors for cancer gene therapy that are designed to spread rapidly from cell to cell by virtue of the fact that they express ADP, an Ad protein that is expressed predominantly late in infection and that is required for efficient virus release at the culmination of the replication cycle. The vectors fall into one of two basic groups, those that express mutant E1A proteins, which restricts vector replication to dividing cells, or those that express wild-type E1A proteins. The vectors KD3 and VRX-007 are the prototypes of the former and latter group, respectively. With aim of improving our vectors to more effectively destroy cells within the tumor mass as well as kill tumor cells that have metastasized, we constructed four different oncolytic vectors in the KD3 or VRX-007 genetic background that express the cancer therapeutic protein TRAIL. We have demonstrated that our vectors kill cells directly by lysis of infected cells and by TRAIL-induced apoptosis of uninfected cells. In this grant application, we will further characterize the oncolytic properties of the TRAIL-expressing vectors in different tumor cell lines and in normal cells. We will evaluate the TRAIL vectors for their ability to suppress the growth of human tumors growing in nude mice. Mice treated with the vectors will be examined with respect to tumor growth, virus replication, expression of TRAIL, and pathology of the tumors and normal tissues. As critical test, we will inject the vectors into a tumor on one flank of a nude mouse and determine the vector's effect on a tumor located on the contralateral flank.
Thesaurus Terms: Adenoviridae, CD95 molecule, biotechnology, gene expression, gene therapy, neoplasm /cancer therapy, transfection /expression vector, tumor necrosis factor alpha adenosine diphosphate, antineoplastic, apoptosis, cytotoxicity, liver cell, liver neoplasm, lung, lung neoplasm, neoplasm /cancer remission /regression, neoplastic cell, virus replication athymic mouse, female, heterologous transplantation, histopathology, immunofluorescence technique, tissue /cell culture
