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Modulation of Apoptotic Response of a Radiation-resistant Human Carcinoma by Pseudomonas Exotoxin-Chimeric Protein¹

Department of Radiation and Cellular Oncology, University of Chicago Hospitals, Chicago, Illinois 60637 [S. S., E. N., M. A. B., R. H., A. C., R. R. W.]; Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [I. M., I. P.]; and Division of Cancer Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [D. W. K.]

Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PE53L/TGF-/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PE53L/TGF-/KDEL decreases the apoptotic threshold through protein synthesis inhibition and simultaneous production of ceramide in tumor cells that lack functional p53 protein. In contrast, no increase in local or systemic toxicity was observed with the chimeric toxin and radiation. We conclude that biochemical targeting of the chimeric toxin and physical targeting of ionizing radiation may increase the therapeutic ratio in the treatment of human cancers with alterations of p53 expression. This strategy offers a high therapeutic potential for Pseudomonas exotoxin A chimeric proteins and irradiation.

¹ This work was supported by an unrestricted grant from Varian Inc., CA., and NIH Grants CA-42596 (to R. R. W.) and CA-55241 (to D. W. K.).

² To whom requests for reprints should be addressed. Fax: (773) 834-7233; E-mail: rrw@rover.uchicago.edu.

Received 3/27/98. Accepted 6/16/98.