title: Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer.
abstract: Recent studies have indicated that angiogenesis may be regulated, in part, by p53 tumor suppressor gene function. We hypothesized that wild-type p53 replacement would down-regulate vascular endothelial growth factor (VEGF) expression and inhibit angiogenesis. KM12L4 and SW620, human colon cancer cell lines with p53 mutations, were transduced with a replication-defective adenoviral vector containing the wild-type p53 gene (Ad5/CMV/p53). Reverse transcription-PCR confirmed the presence of p53 in Ad5/CMV/p53-transduced cells. Transduction of colon cancer cells with wild-type p53 decreased VEGF RNA expression compared with that of controls. The decrease in VEGF expression in SW620 cells was dose dependent, with a 49% decrease observed at a multiplicity of infection of 50, and a 71% decrease observed at a multiplicity of infection of 100. Similar effects were seen in KM12L4 cells. VEGF supernatant protein levels were significantly reduced compared with those in nontransduced controls 48 h after the introduction of wild-type p53. Ad5/CMV/p53 inhibited tumor cell-induced angiogenesis in vivo. Restoration of wild-type p53 expression may decrease tumor growth by inhibiting the angiogenic response. These findings may explain, in part, the bystander effect seen with p53 tumor suppressor gene therapy.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bouvet
authors.forename: L M
authors.initials: LM
authors.lastname: Ellis
authors.forename: M
authors.initials: M
authors.lastname: Nishizaki
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: C D
authors.initials: CD
authors.lastname: Bucana
authors.forename: B
authors.initials: B
authors.lastname: Fang
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors