Selective toxicity diphtheria toxin

A different kind of enzyme, translocase [80700-39-6], which transfers a fragment of NAD to the protein—synthesis factor (elongation factor 2), is catalyzed by diphtheria toxin, thereby inhibiting protein synthesis (43). In tumor cells, the rate of protein synthesis is 100 to 1000 times more sensitive to diphtheria toxin than the analogous process in normal cells (41) therefore, diphtheria toxin is selectively toxic to tumor cells. 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

E. S. Massuda, E. J. Dunphy, R. A. Redman, J. J. Schreiber, L. E. Nauta, F. G. Barr, I. H. Maxwell, and T. P. Cripe, Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells, Proc. Natl. Acad. Sci. USA 94 14701 (1997). 

Bacha et al. (8) demonstrated that a conjugate toxin composed of the non-toxic diphtheria toxin-related protein CRM45 which was disulfide cross-linked to the polypeptide thyrotropin releasing hormone (TRH) was selectively toxic for TRH receptor bearing eukaryotic cells in vitro. Moreover, the administration of the CRM45-TRH conjugate to rats resulted... 

In the present report, we describe the genetic constmcdon, expression, and cell receptor targeted toxicity of a fusion protein composed of the first 485 amino acids of diphtheria toxin linked to amino acids 2 through 133 of IL-2. The fusion protein, IL-2-toxin, is shown to be selectively toxic toward high affinity IL-2 receptor bearing cells in vitro, and to block an activated T-ceU mediated delayed type hypersensitivity (DTH) reaction in vivo. 

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