title: Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice.
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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Bojidar M
authors.initials: BM
authors.lastname: Kojouharov
authors.forename: Craig M
authors.initials: CM
authors.lastname: Brackett
authors.forename: Jean M
authors.initials: JM
authors.lastname: Veith
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Johnson
authors.forename: Ilya I
authors.initials: II
authors.lastname: Gitlin
authors.forename: Ilia A
authors.initials: IA
authors.lastname: Toshkov
authors.forename: Anatoli S
authors.initials: AS
authors.lastname: Gleiberman
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology*; D011897:Random Allocation; D051198:Toll-Like Receptor 5 / Q000819:agonists*
chemical_list: C528306:CBLB502; D010455:Peptides; D051198:Toll-Like Receptor 5; D005472:Fluorouracil