Targeting Urokinase-Type Plasminogen Activator Receptor on Human Glioblastoma Tumors With Diphtheria Toxin Fusion Protein DTAT

Vallera, Daniel A.; Li, Chunbin; Jin, Ni; Panoskaltsis‐Mortari, Angela; Hall, Walter A.

doi:10.1093/jnci/94.8.597

Cited by 87 publications

(67 citation statements)

References 36 publications

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“…Several potential anti-cancer agents have been developed by fusing ATF with other molecules, such as ATF-PAI2CD, 36 ATF-albumin, 37 ATF-domain 2 of bikunin, 38 and ATF-DTx. 39 Each of these hybrid molecules has been tested in animal experiments and all of them exhibit potential anti-cancer activities. In 1993, Crowley et al, constructed an antibody-like molecule consisting of the cell binding domain of u-PA (1-137 aa) linked to the Fc fragment of IgG.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Hu¹,

Duan²,

Shuyuan³

et al. 2008

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Hu¹,

Duan²,

Shuyuan³

et al. 2008

Cancer Biology & Therapy

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“…IL-13 has been shown to bind IL-4R. 28,36 Our studies showed that toxicity was reduced in the knockouts that did not have IL-4 receptor. These studies indicated that the hepatotoxicity was attributed to specific binding of the IT, and not to the nonspecific presence of DT.…”

Section: Discussionmentioning

confidence: 64%

“…36 U373 MG or Neuro 2a cells at 1 3 10 4 /well or Daudi cells at 1 3 10 5 /well were plated in a 96-well flat-bottomed tissue culture plate. Adherent cells were incubated at 37°C prior to the addition of ITs.…”

Section: Proliferation Inhibition Activitymentioning

confidence: 99%

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

Rustamzadeh

Hall

Todhunter

et al. 2006

Intl Journal of Cancer

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A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model. In vitro studies to determine specificity indicated that the protein called DTIL13 was highly selective for human glioblastoma. In vivo, the maximum tolerated dose of DTIL13 was 1 lg/injection given every other day and repeated for 3 days. Doses that exceeded this amount resulted in weight loss and liver damage as determined by histology and enzyme assay. Experiments in IL-4 receptor knockout mice revealed that liver toxicity was receptorrelated. This same dose given to nude mice with established U373 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging (MRI) proved to be extremely useful in (i) determining the ability of DTIL13 to reduce tumor size and (ii) for studying toxicity since diffusion-weighted and gradient echoweighted MRI revealed that vascular leak syndrome was not a limiting toxicity at this dose. These results suggest that DTIL13 is as effective in an intracranial rodent model as it was in a flank model in previous studies and that DTIL13 might be an effective treatment for glioblastoma multiforme. ' 2005 Wiley-Liss, Inc.Key words: diphtheria toxin; glioblastoma; interleukin-13; brain tumor; immunotoxin Glioblastoma multiforme (GBM) is an incurable, heterogeneous, high-grade astrocytic glioma, thought to originate from glial nonneuronal cells. 1 More recent studies have identified a subpopulation of cancer stem-cells within GBM that retain the capacity for self-renewal and the ability to differentiate into a phenotypically diverse population of cells. 2-4 With a 2-year-patient survival rate of <30%, 5 effective treatment has been hindered by the lack of tumor-specific markers in the majority of patients. Recently, the IL-13 receptor (IL-13R) has been found to be overexpressed on cultured human GBM cell lines and surgical GBM specimens, but is not detectable in normal brain tissue. [6][7][8] Targeting the IL-13 receptor with an immunotoxin (IT) has already proven to have potential for treating brain tumors. [8][9][10][11][12] ITs are not mainstream pharmaceuticals, and treatment of systemic tumors with ITs has been limited by their failure to localize in tumor. The promise of these drugs is considerably greater for brain-cancer therapy, since IT can be directly administered intracranially. In an earlier study, we assembled an IL-13 IT made by fusing gene fragments encoding for human IL-13 and the first 389 amino acids of diphtheria toxin. 13 In vivo studies with this agent showed that it had a potent antitumor effect against IL-13R-positive GBM cells grown in the flanks of nude mice without significant toxicity.Although encouraging, the flank model has limitations as a model for intracranial therapy. First, intratumoral pressure within the flank model does not reach the pressures that occur in intracranial tumors ...

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“…In vitro, DTAT has shown a potent antitumor activity against uPAR-expressing glioblastoma cells (U118MG, U373MG, and U87MG) and human umbilical vein endothelial cells. In vivo, DTAT caused a significant regression of small U118MG cell-induced tumors in mice (Vallera et al, 2002). Tf-CRM107 is a conjugate of human transferrin (Tf) and a genetic mutant of diphtheria toxin (CRM107) that lacks native toxin binding.…”

Section: Diphtheria Toxinmentioning

confidence: 99%

Anticancer peptides from bacteria

Karpiński

Szkaradkiewicz

2013

Bangladesh J Pharmacol

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AzurinAzurin (14 kDa, 128 amino acids) is a copper-containing single-domain protein with a rigid β-barrel structure, produced by Pseudomonas aeruginosa. Azurin contains a AbstractCancer is a leading cause of death in the world. The rapid development of medicine and pharmacology allows to create new and effective anticancer drugs. Among modern anticancer drugs are bacterial proteins. Until now has been shown anticancer activity among others azurin and exotoxin A from Pseudomonas aeruginosa, Pep27anal2 from Streptococcus pneumoniae, diphtheria toxin from Corynebacterium diphtheriae, and recently discovered Entap from Enterococcus sp. The study presents the current data regarding the properties, action and anticancer activity of listed peptides.

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Targeting Urokinase-Type Plasminogen Activator Receptor on Human Glioblastoma Tumors With Diphtheria Toxin Fusion Protein DTAT

Abstract: DTAT may have potential for intracranial glioblastoma therapy because of its ability to target tumor cells and tumor vasculature simultaneously and its apparent lack of systemic effects.

Cited by 87 publications

References 36 publications

Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

Anticancer peptides from bacteria

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