Adenovirus-mediated N5 gene transfer inhibits tumor cell proliferation by induction of apoptosis

Gene therapy designed to initiate apoptotic cell death provides a potential ly effective method to treat cancer. A prerequisite for this approach is th e identification of genes that function iri distinct apoptotic pathways. Al though apoptotic pathways initiated by receptors such as tumor necrosis fac tor receptor-1 are well characterized, little is known about apoptotic path ways initiated within the nucleus in response to genotoxic stress. We have demonstrated previously that the nuclear, death domain-containing protein p 84N5 can induce apoptosis upon transfection into cells, suggesting that it may play a role in an apoptotic pathway initiated within the nucleus. To te st the possibility that N5 could be used in the gene therapy of cancer, we have generated a recombinant adenovirus engineered to express N5 and tested the effects of viral infection on the growth and tumorigenicity of tumor c ells. N5 adenovirus infection significantly reduced the proliferation and t umorigenicity of breast, ovarian, and osteosarcoma tumor cell lines. Reduce d proliferation and tumorigenicity were mediated by an induction of apoptos is as indicated by DNA fragmentation in infected cells. The results suggest that the N5 cDNA is a candidate for the gene therapy of cancer.