Antitumor activity of a transforming growth factor alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE40).
TGF-alpha-PE40 is a chimeric protein composed of transforming growth factor alpha (TGF-alpha) linked to a modified Pseudomonas toxin from which the cell recognition domain has been deleted (PE40). TGF-alpha-PE40 has been shown to have cytotoxic effects on human cancer cell lines that express the epidermal growth factor (EGF) receptor on their surface, and when given i.p., it prolongs the survival of nude mice bearing i.p. tumors. Because several normal tissues, including liver, express EGF receptors on their surfaces, it has not been clear that this agent can be used systemically to treat EGF receptor-bearing tumors. In this study, we have delivered TGF-alpha-PE40 for 7 days by continuous infusion through a miniosmotic pump placed in the peritoneal cavity of nude immunodeficient mice. Two different human cancer cell lines that express EGF receptors on their surface were implanted s.c. One was A431, an epidermoid carcinoma; the other was DU-145, a prostate carcinoma. By using this mode of continuous i.p. delivery, we were able to achieve a constant serum level of TGF-alpha-PE40 that was nontoxic to the mice and yet delayed the growth of both tumors implanted s.c. and caused partial regression of one. We conclude that it is possible to deliver TGF-alpha-PE40 systemically and achieve a therapeutic serum level in mice without major toxicity. Although side effects may be expected, this study establishes that there is a therapeutic window for this agent in the therapy of cancers with high numbers of EGF receptors.
Pai
L H
LH
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Gallo
M G
MG
FitzGerald
D J
DJ
Pastan
I
I
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005098:Exotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; C062005:transforming growth factor type alpha-Pseudomonas exotoxin A