TRANSFORMING GROWTH FACTOR-ALPHA PSEUDOMONAS EXOTOXIN FUSION PROTEIN PROLONGS SURVIVAL OF NUDE-MICE BEARING TUMOR XENOGRAFTS

Transforming growth factor α (TGFα)-Pseudomonas exotoxin 40 (PE40) is a chimeric protein consisting of an N-terminal TGFα domain fused to a C-terminal 40-kDa segment of the Pseudomonas exotoxin A protein. TGFα-PE40 exhibits the receptor-binding activity of TGFα and the cell-killing activity of PE40. These properties make TGFα-PE40 an effective cytotoxic agent for cells that possess epidermal growth factor receptors (EGFR). However, the utility of this protein as an anticancer agent has been unclear because many normal tissues express EGFR and may be damaged by exposure to TGFα-PE40. To address this issue, we injected nude mice with a lethal inoculum of either A431 or HT29 human tumor cells that possess EGFR or with Chinese hamster ovary (CHO) tumor cells that lack EGFR. Animals were treated with a derivative of TGFα-PE40 in which the cysteine residues are replaced by alanine, termed 'TGFα-PE40δcys', or with saline once a day for 5 days. Mice bearing EGFR+ tumor cells lived significantly (P < 0.001) longer when treated with TGFα-PE40δcsy compared with saline-treated controls (median survival: A431 cells, 51.5 vs. 25.5 days; HT29 cells, 101 vs. 47.5 days). TGFα-PE40δcys did not prolong the survival of mice bearing tumor cells that lack EGFR (median survival: CHO cells, 15.5 vs. 19.5 days). The only toxicity to normal tissues was mild periportal hepatic necrosis. These studies indicate that a therapeutic window exists in vivo for the use of some growth factor-toxin fusion proteins as anticancer agents.