ADENOVIRUS-MEDIATED WILD-TYPE P53 GENE-TRANSFER DOWN-REGULATES VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION AND INHIBITS ANGIOGENESIS IN HUMAN COLON-CANCER

Recent studies have indicated that angiogenesis may be regulated, in D art, by p53 tumor suppressor gene function. We hypothesized that wild- type p53 replacement would down-regulate vascular endothelial growth f actor (VEGF) expression and inhibit angiogenesis, KM12L4 and SW620, hu man colon cancer cell lines with p53 mutations, were transduced with a replication-defective adenoviral vector containing the wildtype p53 g ene (Ad5/CRni/p53). Reverse transcription-PCR confirmed the presence o f p53 in Ad5/CMV/p53-transduced cells. Transduction of colon cancer ce lls with wild-type p53 decreased VEGF RNA expression compared with tha t of controls. The decrease in VEGF expression in SW620 cells was dose dependent, with a 49% decrease observed at a multiplicity of infectio n of 50, and a 71% decrease observed at a multiplicity of infection of 100, Similar effects were seen in KM12L4 cells. VEGF supernatant prot ein levels were significantly reduced compared with those in nontransd uced controls 48 h after the introduction of wild-type p53, Ad5/CMV/p5 3 inhibited tumor cell-induced angiogenesis in vivo. Restoration of wi ld-type p53 expression may decrease turner growth by inhibiting the an giogenic response. These findings may explain, in part, the bystander effect seen with p53 tumor suppressor gene therapy.