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

doi:10.18632/oncotarget.1773

Bojidar M Kojouharov, Christopher P Johnson + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.1773

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Journal: Oncotarget	Publication Date: Feb 15, 2014
Citations: 34	License type: cc-by

Affiliation: Roswell Park Cancer Institute, Buffalo BioLabs

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.

Highlights

Severe adverse side effects continue to be a major challenge of use of many conventional anticancer drugs
Systemic administration of Entolimod leads to NF-B- and STAT3-mediated induction of numerous bioactive factors including antiapoptotic proteins, scavengers of reactive oxygen species (ROS), cytokines and antiinflammatory agents which can contribute to protection of normal tissues from the damaging effects of radiation- or drug-related genotoxicity [10, 38]
Using 5-FU as a model, we show that Entolimod is capable of reducing the toxicity of genotoxic chemotherapy to GI and HP tissues resulting in overall improvement in health and survival of treated mice

Summary

Introduction

Severe adverse side effects continue to be a major challenge of use of many conventional anticancer drugs. These include gastrointestinal (GI) damage with such symptoms as diarrhea, vomiting, GI mucositis and body weight loss, and hematopoietic (HP) damage causing leukopenia, thrombocytopenia, myelosuppression leading to immunosuppression and uncontrolled bacteremia [14]. These toxicities frequently prevent administration of sufficiently effective drug doses and can severely affect quality of life or even be fatal [4,5,6]. TLR5 agonistic agents like Entolimod have a notable advantage over other TLR agonists that have been considered for clinical use (TLR3, 4 and 7 [13]) in that the specific profile of cytokines induced following TLR5 stimulation does not include those that can lead to a harmful uncontrolled “cytokine storm”, such as IL-1 and TNF [13, 14]

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