Abstract
Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PEΔ53L/TGF-α/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PEΔ53L/TGF-α/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.
Footnotes
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↵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.).
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↵2 To whom requests for reprints should be addressed. Fax: (773) 834-7233; E-mail: rrw@rover.uchicago.edu.
- Received March 27, 1998.
- Accepted June 16, 1998.
- ©1998 American Association for Cancer Research.
Volume 58, Issue 15
