Protein Engineering, Vol. 15, No. 5, 419-427,
May 2002
© 2002 Oxford University Press
Targeting glioblastoma multiforme with an IL-13/diphtheria toxin fusion protein in vitro and in vivo in nude mice
1 Department of Therapeutic Radiology–Radiation Oncology, Section on Experimental Cancer Immunology, 3 Department of Neurosugery and 4 Department of Pediatrics, University of Minnesota Cancer Center, University of Minnesota. Minneapolis, MN 55455, USA
Fusion proteins composed of tumor binding agents and potent catalytic toxins show promise for intracranial therapy of brain cancer and an advantage over systemic therapy. Glioblastoma multiforme (GBM) is the most common form of brain cancer and overexpresses IL-13R. Thus, we developed an interleukin-13 receptor targeting fusion protein, DT390IL13, composed of human interleukin-13 and the first 389 amino acids of diphtheria toxin. To measure its ability to inhibit GBM, DT390IL13 was tested in vitro and found to inhibit selectively the U373 MG GBM cell line with an IC50 around 12 pmol/l. Cytotoxicity was neutralized by anti-human-interleukin-13 antibody, but not by control antibodies. In vivo, small U373 MG glioblastoma xenografts in nude mice completely regressed in most animals after five intratumoral injections of 1 µg of DT390IL13 q.o.d., but not by the control fusion protein DT390IL-2. DT390IL13 was also tested against primary explant GBM cells of a patient's excised tumor and the IC50 was similar to that measured for U373 MG. Further studies showed a therapeutic window for DT390IL13 of 1–30 µg/injection and histology studies and enzyme measurements showed that the maximum tolerated dose of DT390IL13 had little effect on kidney, liver, spleen, lung and heart in non-tumor-bearing immunocompetent mice. Together, these data suggest that DT390IL13 may provide an important, alternative therapy for brain cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. J. Stish, H. Chen, Y. Shu, A. Panoskaltsis-Mortari, and D. A. Vallera A Bispecific Recombinant Cytotoxin (DTEGF13) Targeting Human Interleukin-13 and Epidermal Growth Factor Receptors in a Mouse Xenograft Model of Prostate Cancer Clin. Cancer Res., November 1, 2007; 13(21): 6486 - 6493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 D. A. Todhunter, W. A. Hall, E. Rustamzadeh, Y. Shu, S. O. Doumbia, and D. A. Vallera A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model Protein Eng. Des. Sel., February 1, 2004; 17(2): 157 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Liu, K. A. Cohen, J. G. Ramage, M. C. Willingham, A. M. Thorburn, and A. E. Frankel A Diphtheria Toxin-Epidermal Growth Factor Fusion Protein Is Cytotoxic to Human Glioblastoma Multiforme Cells Cancer Res., April 15, 2003; 63(8): 1834 - 1837. [Abstract] [Full Text] [PDF]
|
|