tailieunhanh - Báo cáo khoa học: A guide to taming a toxin – recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer

Pseudomonasexotoxin A (PE) is a highly toxic protein secreted by the opportunistic pathogen Pseudomonas aeruginosa. The modular structure and corresponding mechanism of action of PE make it amenable to exten-sive modifications that can redirect its potent cytotoxicity from disease to a therapeutic function. | fFEBS Journal REVIEW ARTICLE A guide to taming a toxin - recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer John E. Weldon and Ira Pastan Laboratory of Molecular Biology Center for Cancer Research NationalCancer Institute National institutes of Health Bethesda MD USA Keywords antibody conjugates cancer therapy intracellular trafficking moxetumomab pasudotox Pseudomonas exotoxin A recombinant immunotoxins Correspondence I. Pastan Laboratory of Molecular Biology NationalCancer Institute 37 Convent Drive Room 5106 Bethesda MD 20892-4264 USA Fax 1 301 402 1344 Tel 1 301 496 4797 E-mail pastani@ Received 6 April 2011 accepted 16 May 2011 doi Pseudomonas exotoxin A PE is a highly toxic protein secreted by the opportunistic pathogen Pseudomonas aeruginosa. The modular structure and corresponding mechanism of action of PE make it amenable to extensive modifications that can redirect its potent cytotoxicity from disease to a therapeutic function. In combination with a variety of artificial targeting elements such as receptor ligands and antibody fragments PE becomes a selective agent for the elimination of specific cell populations. This review summarizes our current understanding of PE its intoxication pathway and the ongoing efforts to convert this toxin into a treatment for cancer. Introduction The natural world abounds with an enormous variety of toxins comprising poisonous substances that are naturally produced by living organisms 1 . Typically only small quantities of toxins are necessary to damage cells although the specific target and the toxic dose may vary extensively. Microorganisms secrete toxins as virulence factors during pathogenic infection and as secondary metabolites that can contaminate local environments. Well known examples include diphtheria toxin and ergot alkaloids. Higher organisms use toxins as components in complex venoms and accumulate them as defense factors .

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