Adenovirus-mediated N5 gene transfer inhibits tumor growth and metastasis of human carcinoma in nude mice.
The therapeutic effectiveness of cancer therapy often relies on induction of apoptotic cell death. Gene-therapy-mediated induction of apoptosis, therefore, may provide an effective means to kill cancer cells. The N5 gene encodes a death-domain-containing protein (p84N5) that can trigger atypical apoptosis from within the nucleus, suggesting it may be a candidate for use as a gene therapy for cancer. In the present study, we test the potential utility of a recombinant adenovirus designed to express the N5 gene(AdN5) for the treatment of a variety of human cancers using in vitro and animal models. In vitro, adenoviral-mediated N5 gene transfer inhibits the growth of five different tumor cell lines, but not a normal diploid fibroblast cell line. Adenoviral-mediated N5 gene transfer also reduces the growth and metastasis of primary human tumors in subcutaneous and orthotopic xenograft mouse models. Reduction in tumor cell growth in vitro and in vivo correlates with increased expression of p84N5 and induction of apoptosis. The relative sensitivity of different human cancer cells to AdN5 or Adp53 varies, suggesting that AdN5 may be effective in tumors relatively resistant to p53 gene therapy. We conclude that N5 has potential utility for the gene therapy of cancer.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Shenmin
S
Yin
Wang
W
Bailiang
Keping
K
Xie
David W
DW
Goodrich
D000230:Adenocarcinoma / Q000473:pathology*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics*; D004268:DNA-Binding Proteins; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016601:RNA-Binding Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C400546:THOC1 protein, human