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Departments of Surgical Oncology [M. B., L. M. E.], Cell Biology [L. M. E., W. L., C. D. B.], Biomathematics [J. J. L.], and Thoracic and Cardiovascular Surgery [B. F., J. A. R.] and Section of Thoracic Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and First Department of Surgery, Okayama University Medical School, Okayama 700, Japan [M. N., T. F.]
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.
1 This study was partially supported by a National Cancer Institute Training Grant T32-09599-08 and an American Cancer Society Oncology Fellowship (to M. B.), by gifts to the Division of Surgery from Tenneco and Exxon for its Core Laboratory Facility, by University of Texas M. D. Anderson Cancer Center Support Core Grant CA16672 from the National Cancer Institute, by Specialized Program of Research Excellence in Lung Cancer Grant P50-CA70907 from the NIH, American Cancer Society Career Development Award, The Gillson Longenbaugh Foundation, by a grant from the Mathers Foundation, and by a sponsored research agreement with Introgen Therapeutics, Inc.
2 To whom requests for reprints should be addressed, at the Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Box 109, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-6932; Fax: (713) 794-4901.
Received 3/17/98. Accepted 4/15/98.
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