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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2143-2148. Prepublished online as a Blood First Edition Paper on May 25, 2004; DOI 10.1182/blood-2004-01-0339. This Article Full Text (PDF) All Versions of this Article: 2004-01-0339v1 104/7/2143    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Abi-Habib, R. J Articles by Frankel, A. E Search for Related Content PubMed PubMed Citation Articles by Abi-Habib, R. J Articles by Frankel, A. E Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 28, 2004 Accepted April 5, 2004 A urokinase activated-recombinant diphtheria toxin targeting the granulocyte-macrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts Ralph J Abi-Habib, Shihui Liu, Thomas H Bugge, Stephen H Leppla, and Arthur E Frankel* Biochemistry and Molecular Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Microbial Pathogenesis Section, National Institutes of Allergy and Infectious Diseases, Bethesda, MD, USA Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA * Corresponding author; email: afrankel{at}wfubmc.edu. Novel agents to treat acute myeloid leukemia (AML) are needed with increased efficacy and specificity. We have synthesized a dual specificity fusion toxin DTU2GMCSF composed of the catalytic and translocation domains of diphtheria toxin (DT) fused to the granulocyte macrophage colony stimulating factor (GMCSF) in which the DT furin cleavage site (163RVRRSV170) is modified to a urokinase plasminogen activator (uPA) cleavage site termed U2 (163GSGRSA170). DTU2GMCSF was highly toxic to the TF1-vRaf AML cell line (proliferation inhibition assay; IC50=3.14 pM), and this toxicity was greatly inhibited following pretreatment with anti-uPA and anti-GMCSF antibodies. The activity of this toxin was then tested on a larger group of 13 human AML cell lines and 5 of the 13 cell lines were sensitive to DTU2GMCSF. An additional 5 of the 13 cell lines became sensitive when exogenous pro-uPA was added. Sensitivity to DTU2GMCSF strongly correlated with the expression levels of uPA receptors (uPAR) and GMCSF receptors (GMCSFR) as well as with total uPA levels. DTU2GMCSF was less toxic to normal cells expressing uPAR or GMCSFR alone, i.e. HUV-EC and peripheral macrophages, respectively. These results indicate that DTU2GMCSF may be a selective and potent agent for the treatment of patients with AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Site-specific conversion of a pro-fusion protein toxin John R. Murphy Blood 2004 104: 1919-1920. [Full Text] [PDF] This article has been cited by other articles: R. J. Abi-Habib, R. Singh, S. H. Leppla, J. J. Greene, Y. Ding, B. Berghuis, N. S. Duesbery, and A. E. Frankel Systemic Anthrax Lethal Toxin Therapy Produces Regressions of Subcutaneous Human Melanoma Tumors in Athymic Nude Mice Clin. Cancer Res., December 15, 2006; 12(24): 7437 - 7443. [Abstract] [Full Text] [PDF] R. J. Abi-Habib, R. Singh, S. Liu, T. H. Bugge, S. H. Leppla, and A. E. Frankel A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types. Mol. Cancer Ther., October 1, 2006; 5(10): 2556 - 2562. [Abstract] [Full Text] [PDF] M. M. Westcott, R. J. Abi-Habib, K. A. Cohen, M. C. Willingham, S. Liu, T. H. Bugge, S. H. Leppla, and A. E. Frankel Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells Mol. Cancer Ther., December 1, 2004; 3(12): 1681 - 1689. [Abstract] [Full Text] [PDF]

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