Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice
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Bojidar M. Kojouharov1, Craig M. Brackett1, Jean M. Veith1, Christopher P. Johnson1, Ilya I. Gitlin1, Ilia A. Toshkov2, Anatoli S. Gleiberman2, Andrei V. Gudkov1,2,3 and Lyudmila G. Burdelya1,2
1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY
2 Buffalo BioLabs, LLC, Buffalo, NY
3 Cleveland BioLabs, Inc., Buffalo, NY
Lyudmila Burdelya, email:
Keywords: TLR5, flagellin, chemotherapy, hematopoietic, gastrointestinal toxicity, tumor
Received: January 27, 2014 Accepted: February 23, 2014 Published: February 23, 2014
Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis. Entolimod-stimulated IL-6 production was essential for Entolimod’s ability to rescue mice from death caused by doses of 5-FU associated with hematopoietic failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged gastrointestinal tissue by Entolimod. In a syngeneic mouse CT26 colon adenocarcinoma model, Entolimod reduced the systemic toxicity of 5-FU, but did not reduce its antitumor efficacy indicating that the protective effect of Entolimod was selective for normal, non-tumor, tissues. These results suggest that Entolimod has clinical potential to broaden the therapeutic window of genotoxic anticancer drugs by reducing their associated hematopoietic and gastrointestinal toxicities.
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