Small chimeric toxins containing only transforming growth factor alpha and domain III of Pseudomonas exotoxin with good antitumor activity in mice.
Chimeric toxins composed of transforming growth factor alpha (TGF alpha) fused to mutant forms of Pseudomonas exotoxin (PE) bind to the epidermal growth factor receptor and kill cells bearing epidermal growth factor receptors. Initially, the binding domain (Ia; amino acids 1-252) of PE was deleted and replaced with TGF alpha to make TGF alpha-PE40 in which TGF alpha is fused to domains II, Ib, and III of PE (amino acids 253-613). That drug is currently undergoing clinical study for the intravesical therapy of bladder cancer. To generate smaller molecules that would have increased tumor penetration, several deletion mutants were constructed. In one of these, TGF alpha was inserted near the carboxyl terminus of PE, and residues in domains II and Ib of PE (amino acids 253-279 and 365-380) were deleted so that the chimeric toxin did not need to be cleaved by an intracellular protease to be activated (Theuer et al., J. Biol. Chem., 267: 16872-16877, 1992). We have now constructed chimeric toxins which contain only domain III, yet still exhibit high cytotoxic activity on epidermal growth factor receptor-containing cells and produce substantial tumor regressions in mice bearing a human xenograft. The high cytotoxic activity of these severely truncated toxins provides new insights on the proposed functions of domains II and III of PE.
Kihara
A
A
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Pastan
I
I
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D004355:Drug Stability; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; C062005:transforming growth factor type alpha-Pseudomonas exotoxin A; D000246:Adenosine Diphosphate Ribose; D066246:ErbB Receptors