In vivo activities of acidic fibroblast growth factor-Pseudomonas exotoxin fusion proteins.
Fibroblast growth factor receptors are highly expressed in a variety of cancer cells and activated vasculature. Using chimeric toxins targeted to cell-surface a FGF receptors, we have demonstrated specific cytotoxic activity to these cell types. These molecules, aFGF-PE40 and aFGF-PE40 KDEL, are fusion proteins containing acidic FGF and either a 40- or a 66-kDa binding defective form of Pseudomonas exotoxin, respectively. Both aFGF-toxin fusion proteins were able to inhibit protein synthesis in vitro in a variety of carcinoma cell lines. The half-life of aFGF-PE40 in serum was found to be 41 min when coadministered with heparin. Administration of aFGF-PE40 or aFGF-PE4E KDEL with heparin inhibits the growth of established KB and preestablished A431 epidermoid carcinoma xenografts in athymic mice. The antitumor activities of the two aFGF-toxin fusion proteins were equivalent against the KB tumor xenografts. While we were able to slow the growth of the KB tumor xenografts, we were unable to cause tumor regressions. Histochemical analysis of treated versus untreated tumor tissue revealed a difference in tumor size but not of vascularity. We conclude that aFGF-PE40 and aFGF-PE4E KDEL have in vivo antitumor activity that targets the tumor cell mass rather than vascular structures in mice xenografted with human epidermoid carcinoma.
Siegall
C B
CB
Bristol-Myers Squibb, Molecular Immunology Department, Seattle, Washington 98121.
Gawlak
S L
SL
Chace
D F
DF
Merwin
J R
JR
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001427:Bacterial Toxins; D004337:Drug Carriers; D005098:Exotoxins / Q000097:blood / Q000494:pharmacology*; D016220:Fibroblast Growth Factor 1 / Q000097:blood / Q000494:pharmacology*; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D004337:Drug Carriers; D005098:Exotoxins; D016220:Fibroblast Growth Factor 1; D009363:Neoplasm Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A