Oncotarget

Research Papers:

Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice

Bojidar M. Kojouharov, Craig M. Brackett, Jean M. Veith, Christopher P. Johnson, Ilya I. Gitlin, Ilia A. Toshkov, Anatoli S. Gleiberman, Andrei V. Gudkov and Lyudmila G. Burdelya _

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Oncotarget. 2014; 5:802-814. https://doi.org/10.18632/oncotarget.1773

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Abstract

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

Correspondence:

Lyudmila Burdelya, email:

Keywords: TLR5, flagellin, chemotherapy, hematopoietic, gastrointestinal toxicity, tumor

Received: January 27, 2014 Accepted: February 23, 2014 Published: February 23, 2014

Abstract

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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