Modulation of apoptotic response of a radiation-resistant human carcinoma by Pseudomonas exotoxin-chimeric protein.
Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PEdelta53L/TGF-alpha/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PEdelta53L/TGF-alpha/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.
Department of Radiation and Cellular Oncology, University of Chicago Hospitals, Illinois 60637, USA.
S
S
Seetharam
E
E
Nodzenski
M A
MA
Beckett
R
R
Heimann
A
A
Cha
I
I
Margulies
I
I
Pastan
D W
DW
Kufe
R R
RR
Weichselbaum
D036002:ADP Ribose Transferases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D001427:Bacterial Toxins; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002518:Ceramides / Q000494:pharmacology; D003131:Combined Modality Therapy; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000096:biosynthesis / Q000378:metabolism; D021382:Protein Sorting Signals; D011836:Radiation Tolerance / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D002518:Ceramides; D066246:ErbB Receptors; D005098:Exotoxins; D009842:Oligopeptides; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C073762:lysyl-aspartyl-glutamyl-leucine