Interleukin-4 receptors expressed on tumor cells may serve as a target for anticancer therapy using chimeric Pseudomonas exotoxin.
Interleukin-4 receptors (IL4R) are present on a wide variety of human cancer cells derived from both hematopoietic and epithelial malignancies. We have targeted IL4R on a human solid tumor xenograft with chimeric proteins composed of human IL4 (hIL4) and 2 different mutant forms of a powerful bacterial toxin, Pseudomonas exotoxin A (PE). The 2 chimeric toxins, termed hIL4-PE4E and hIL4-PE38QQR, showed specific, hIL4R-dependent and dose-dependent antitumor activities. Neither of the chimeric toxins showed antitumor potency when the ADP-ribosylation activity of the toxin was inactivated by mutagenesis. One of the chimeras, hIL4-PE38QQR, caused a complete although transient regression of established solid tumors. These observations indicate that hIL4-PE chimeric proteins should be further evaluated for the treatment of human malignancies.
Debinski
W
W
Laboratory of Molecular Targeting, Hotel-Dieu Hospital of Montreal, University of Montreal, QC, Canada.
Puri
R K
RK
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D005098:Exotoxins / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D015847:Interleukin-4 / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D014183:Transplantation, Heterologous; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D015847:Interleukin-4; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A