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Adenovirus-based Transfer of Wild-Type p53 Gene Increases Ovarian Tumor Radiosensitivity¹

Departments of Radiation Oncology [D. G., W. H. M.] and Surgery [K. E. D.], UCLA Medical Center, Los Angeles, California 90095-171415

The p53 tumor suppressor gene product is known to be active in mediating radiation-induced G₁-S cell cycle arrest and apoptosis in a number of normal cell lines. These functions are compromised by inactivation of p53, which promotes tumor progression. Because the p53 gene appears to play an important role in the cellular response to radiation, wild-type p53 gene replacement might be expected to increase the sensitivity of malignant cells with mutant p53 to the cytotoxic effects of ionizing radiation. This study demonstrates that adenovirus (AdV)-mediated transfer and expression of the wild-type p53 in malignant cells lacking the p53 gene results in an increase in cellular radiosensitivity in vitro and tumor radioresponsiveness in vivo.

Cultures of the p53 double deletion mutant ovarian cell line SK-OV-3 were infected with nonreplicative adenoviral vectors containing either the wild-type p53 gene (AdVp53) or the luciferase gene (AdVluc). Cultures infected with AdVp53 efficiently expressed wild-type p53 protein and were more sensitive to radiation than uninfected cultures or cultures infected with AdVluc.

The ability of AdVp53 to radiosensitize tumors in vivo was tested using SK-OV-3 tumors growing in the flanks of severe combined immune-deficient mice. Intratumoral injection with AdVp53, but not AdVluc, led to enhanced radioresponsiveness and 45% long-term tumor control. These studies demonstrate the ability of AdVp53 to effectively transfer and express p53 protein in established tumors with a resultant increase in radiation responsiveness.

¹ This study was supported by grants from the American Society for Therapeutic Radiology and the Radiological Society of North America (both to D. G.).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Room B3-109, Center for Health Sciences, Los Angeles, CA 90095-171415.

Received 7/ 8/96. Accepted 9/17/96.

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