Vascular leak syndrome , immunotoxin

Toxins as effector molecules have been widely studied in vitro and applied in vivo in pre-clin-ical and clinical studies. A frequent observation with immunotoxins in the clinic is the occurrence of vascular leak syndrome. This toxicity is associated with the toxin moiety of the im-munotoxin and sometimes demands cessation of therapy or administration of snb-optimal dosages [92]. Another approach with high potential is to selectively inhibit tnmonr blood flow by selectively targeting the blood coagnlation-mdndng activity of the tnmonr endothelium. 

Siegall CB, Liggett D. Characterization of vascular leak syndrome induced by the toxin component of pseudomonas exotoxin-based immunotoxin and its protential inhibition with nonsteroidal anti-inflammatory drugs. Clin Cancer Res 1997 3 339-45. 

Siegall CB, Liggitt D. Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitiumor activity. Proc Natl Acad Sci USA 1994 91 9514-18. 

Soler-Rodriguez, A.M., Ghetie, M.A., Oppenheimer-Marks, N., Uhr, J.W. and Vitetta, E.S. (1993) Ricin A-chain and ricin A-chain immunotoxins rapidly damage human endothelial cells implications for vascular leak syndrome. Exp Cell Res, 206, 227-234. 

In a study of 56 patients treated with ricin A chain immunotoxin, 12 required interruption or termination of treatment due to the severity of side-effects, and two patients died as a result of vascular leak syndrome (Baluna et al, 1996). Vascular leak syndrome was more common in patients who had received radiotherapy prior to immunotherapy (Schindler et al, 2001). 

First-generation immunotoxins were hybrid molecules of bacterial toxins covalently linked to antibodies. In a number of studies, these turned out to be insufficient, with dose-limiting toxicides such as vascular leak syndrome, thrombocytopenia, and organ damage. Modern immunotoxins are recombinant fusion products of, for example, the variable domain (Fv) of a MAb, and a truncated bacterial toxin [121]. Recombinant immunotoxins are currendy being developed to target a number of... 

The exact cause of death is unknown and probably varies with route of intoxication. Results of ricin A-chain immunotoxin clinical trial studies demonstrated that ricin A-chain caused a vascular leak syndrome characterized by hypoalbuminemia and edema subsequent in vitro studies with human umbilical vein endothelial cells showed that ricin damaged endothelial cells.45 In mice, rats, and primates, high doses via inhalation appear to produce severe enough pulmonary damage to cause death,... 

Kuan CT, Pai LH, Pastan I (1995) Immunotoxins containing Pseudomonas exotoxin that target LeY damage human endothelial cells in an antibody-specific mode relevance to vascular leak syndrome. Clin Cancer Res 1 1589-1594... 

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