Researchers have found a way that could potentially avoid the debilitating side effects seen in patients taking a type of experimental cancer therapy. Although natural toxins hooked up to antibodies (termed immunotoxins) have promised efficacious and targeted therapies for use in cancer, until now, some have been plagued by a potentially lethal side-effect in humans called vascular leak syndrome (VLS). In the April issue of Nature Biotechnology, scientists at the University of Texas Southwestern Medical Center have isolated and modified key residues in the toxin ricin to eliminate its ability to cause severe side effects without compromising its power to kill tumor cells in mice.
Ricin is a natural toxin found in castor beans. Ricin toxin A chain (RTA) linked to an antibody that targets lymphoma has been investigated in clinical trials, but VLS limited the efficacy of the treatment. If VLS can be minimized, permitting the safe dose escalation of immunotoxins, this should significantly improve their therapeutic profile.
To eliminate these side effects, Ellen Vitetta and coworkers first determined that several proteins that cause VLS contain similar sequences. Next, they engineered RTA-based immunotoxins to alter these sequences. They used a model of VLS in mice to show that the modified RTA-containing immunotoxins kill tumor cells but induce significantly less VLS than unmodified immunotoxins. The toxicity of the immunotoxins is reduced about five-fold. Because several therapeutics can cause VLS, a solution to this problem may facilitate clinical development of other drugs.
Ellen S. Vitetta
Cancer Immunobiology Center
University of Texas Southwestern Medical Center at Dallas
Tel: +1 214 648 1200
Also available online.
(C) Nature Biotechnology press release.
Message posted by: Trevor M. D'Souza