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Toxins, Volume 3, Issue 4 (April 2011), Pages 345-419

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Research

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Open AccessArticle Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity
Toxins 2011, 3(4), 345-355; doi:10.3390/toxins3040345
Received: 24 February 2011 / Revised: 18 March 2011 / Accepted: 23 March 2011 / Published: 24 March 2011
Cited by 12 | PDF Full-text (349 KB) | HTML Full-text | XML Full-text
Abstract
The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency [...] Read more.
The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a “protein-stapling” technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications. Full article
(This article belongs to the Special Issue Development of Botulinum Toxin Drugs)
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Open AccessArticle Detection of Ricin Contamination in Ground Beef by Electrochemiluminescence Immunosorbent Assay
Toxins 2011, 3(4), 398-408; doi:10.3390/toxins3040398
Received: 16 March 2011 / Revised: 31 March 2011 / Accepted: 31 March 2011 / Published: 4 April 2011
Cited by 15 | PDF Full-text (183 KB) | HTML Full-text | XML Full-text
Abstract
Ricin is a highly toxic protein present in the seeds of Ricinus communis (castor), grown principally as a source of high quality industrial lubricant and as an ornamental. Because ricin has been used for intentional poisoning in the past and could be [...] Read more.
Ricin is a highly toxic protein present in the seeds of Ricinus communis (castor), grown principally as a source of high quality industrial lubricant and as an ornamental. Because ricin has been used for intentional poisoning in the past and could be used to contaminate food, there is a need for analytical methodology to detect ricin in food matrices. A monoclonal antibody-based method was developed for detecting and quantifying ricin in ground beef, a complex, fatty matrix. The limit of detection was 0.5 ng/g for the electrochemiluminescence (ECL) method and 1.5 ng/g for enzyme-linked immunosorbent assay (ELISA). The detection of nanogram per gram quantities of ricin spiked into retail samples of ground beef provides approximately 10,000-fold greater sensitivity than required to detect a toxic dose of ricin (>1 mg) in a 100 g sample. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessArticle A Comparison of the Anti-Tumor Effects of a Chimeric versus Murine Anti-CD19 Immunotoxins on Human B Cell Lymphoma and Pre-B Acute Lymphoblastic Leukemia Cell Lines
Toxins 2011, 3(4), 409-419; doi:10.3390/toxins3040409
Received: 3 March 2011 / Revised: 30 March 2011 / Accepted: 30 March 2011 / Published: 6 April 2011
Cited by 3 | PDF Full-text (469 KB) | HTML Full-text | XML Full-text
Abstract
Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that [...] Read more.
Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that complement rather than overlap chemotherapy and bone marrow transplantation. Immunotherapy is a class of therapies where toxicities and mechanisms of action do not overlap with those of chemotherapy. Because CD19 is a B cell- restricted membrane antigen that is expressed on the majority of pre-B tumor cells, a CD19-based immunotherapy is being developed for ALL. In this study, the anti-tumor activities of immunotoxins (ITs) constructed by conjugating a murine monoclonal antibody (MAb), HD37, or its chimeric (c) construct to recombinant ricin toxin A chain (rRTA) were compared both in vitro using human pre-B ALL and Burkitt’s lymphoma cell lines and in vivo using a disseminated human pre-B ALL tumor cell xenograft model. The murine and chimeric HD37 IT constructs were equally cytotoxic to pre-B ALL and Burkitt’s lymphoma cells in vitro and their use in vivo resulted in equivalent increases in survival of SCID mice with human pre-B ALL tumors when compared with control mice. Full article
(This article belongs to the Special Issue Immunotoxins)

Review

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Open AccessReview Cycle Inhibiting Factors (Cifs): Cyclomodulins That Usurp the Ubiquitin-Dependent Degradation Pathway of Host Cells
Toxins 2011, 3(4), 356-368; doi:10.3390/toxins3040356
Received: 18 February 2011 / Revised: 16 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011
Cited by 9 | PDF Full-text (451 KB) | HTML Full-text | XML Full-text
Abstract
Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are “cyclomodulins” that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review [...] Read more.
Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are “cyclomodulins” that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review summarizes current knowledge on Cif since its first characterization in enteropathogenic Escherichia coli, the identification of several xenologues in distant pathogenic bacteria, to its structure elucidation and the recent deciphering of its mode of action. Cif impairs the host ubiquitin proteasome system through deamidation of ubiquitin or the ubiquitin-like protein NEDD8 that regulates Cullin-Ring-ubiquitin Ligase (CRL) complexes. The hijacking of the ubiquitin-dependent degradation pathway of host cells results in the modulation of various cellular functions such as epithelium renewal, apoptosis and immune response. Cif is therefore a powerful weapon in the continuous arm race that characterizes host-bacteria interactions. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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Open AccessReview The Use of Convection-Enhanced Delivery with Liposomal Toxins in Neurooncology
Toxins 2011, 3(4), 369-397; doi:10.3390/toxins3040369
Received: 28 February 2011 / Revised: 25 March 2011 / Accepted: 25 March 2011 / Published: 31 March 2011
Cited by 11 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Liposomes have long been effective delivery vehicles for transport of toxins to peripheral cancers. The combination of convection-enhanced delivery (CED) with liposomal toxins was originally proposed to circumvent the limited delivery of intravascular liposomes to the central nervous system (CNS) due to [...] Read more.
Liposomes have long been effective delivery vehicles for transport of toxins to peripheral cancers. The combination of convection-enhanced delivery (CED) with liposomal toxins was originally proposed to circumvent the limited delivery of intravascular liposomes to the central nervous system (CNS) due to the blood-brain-barrier (BBB). CED offers markedly improved distribution of infused therapeutics within the CNS compared to direct injection or via drug eluting polymers, both of which depend on diffusion for parenchymal distribution. This review examines the basis for improved delivery of liposomal toxins via CED within the CNS, and discusses preclinical and clinical experience with these therapeutic techniques. How CED and liposomal technologies may influence future neurooncologic treatments are also considered. Full article
(This article belongs to the Special Issue Immunotoxins)

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