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

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 (HP) and gastrointestinal (GI) tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects; I demonstrated significant reduction in the severity of 5-FU-induced morbidity. Increased survival was accompanied by the improved integrity of intestinal tissue and the restoration of hematopoiesis in Entolimod treated mice. Entolimod-stimulated IL-6 production was essential for Entolimod’s ability to rescue mice from death caused by doses of 5-FU associated with HP failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged GI 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, noncancerous tissues. These results suggest that Entolimod has clinical potential to broaden the therapeutic window of genotoxic anticancer drugs by reducing their associated HP and GI toxicities.

Grantor dc:publisher

State University of New York at Buffalo

Year dc:date.issued

2018

Author dc:creator

• Kandar, Bojidar

Contributors dc:contributor

• Gudkov, Andrei
• Roswell Park

• oncology
• immunology
• toxicology
• biophysics

Statement dc:rights

• Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.
• Copyright retained by author.

Language dc:language

eng

Handle dc:identifier

http://hdl.handle.net/10477/77951

OAI record oai:identifier

https://ubir.buffalo.edu/oai/request?verb=GetRecord&metadataPrefix=qdc&identifier=oai%3Aubir.buffalo.edu%3A10477%2F77951