Biological activity of a transforming growth factor-alpha--Pseudomonas exotoxin fusion protein in vitro and in vivo.
Transforming growth factor-alpha (TGF alpha)-pseudomonas exotoxin-40 (PE40) is a chimeric protein consisting of an N-terminal TGF alpha domain fused to a C-terminal 40-kDa segment of the pseudomonas exotoxin A protein. TGF alpha-PE40 exhibits the receptor binding activity of TGF alpha and the cell killing activity of PE40. In the current study, we report that a modified TGF alpha-PE40 derivative significantly prolongs the survival of nude mice bearing tumors derived from cell lines which express the epidermal growth factor receptor (EGFR). In addition, the therapeutic benefit of this protein is mediated by specific binding to the EGF receptor. These results indicate that a therapeutic window exists in vivo for the use of some growth factor--toxin fusion proteins as anticancer agents.
Heimbrook
D C
DC
Department of Cancer Research, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Stirdivant
S M
SM
Ahern
J D
JD
Balishin
N L
NL
Patrick
D R
DR
Edwards
G M
GM
Defeo-Jones
D
D
FitzGerald
D J
DJ
Pastan
I
I
Oliff
A
A
D036002:ADP Ribose Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D066246:ErbB Receptors / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011549:Pseudomonas; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D066246:ErbB Receptors; D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A