This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kihara, A. Articles by Pastan, I. Search for Related Content PubMed PubMed Citation Articles by Kihara, A. Articles by Pastan, I.

Small Chimeric Toxins Containing Only Transforming Growth Factor and Domain III of Pseudomonas Exotoxin with Good Antitumor Activity in Mice

Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis, and Centers, National Cancer Institute, NIH, Bethesda, Maryland 20892

Chimeric toxins composed of transforming growth factor (TGF) 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 to make TGF-PE40 in which TGF 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 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.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Biology, National Cancer Institute, NIH, 9000 Rockville Pike, Building 37, Room 4E16, Bethesda, Maryland 20892

Received 5/ 4/94. Accepted 8/ 4/94.

This article has been cited by other articles:

				T. F. Liu, P. D. Hall, K. A. Cohen, M. C. Willingham, J. Cai, A. Thorburn, and A. E. Frankel Interstitial Diphtheria Toxin-Epidermal Growth Factor Fusion Protein Therapy Produces Regressions of Subcutaneous Human Glioblastoma Multiforme Tumors in Athymic Nude Mice Clin. Cancer Res., January 1, 2005; 11(1): 329 - 334. [Abstract] [Full Text] [PDF]