Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice.
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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DOI：
10.18632/oncotarget.1773
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发表时间：
2014-02-15
期刊：
影响因子：
--
通讯作者：
Burdelya LG
中科院分区：
文献类型：
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作者：
Kojouharov BM;Brackett CM;Veith JM;Johnson CP;Gitlin II;Toshkov IA;Gleiberman AS;Gudkov AV;Burdelya LG
骨髓抑制和胃肠道损伤是癌症治疗的常见副作用，限制了DNA损伤化疗药物的疗效。Toll样受体5（TLR 5）激动剂恩托莫德已被证明在减轻由辐射引起的造血和胃肠道组织损伤方面的功效。在这里，使用5-氟尿嘧啶（5-FU）治疗的小鼠作为化疗诱导的副作用的模型，我们证明了5-FU诱导的发病率的严重程度显着降低，并增加生存伴随着改善肠组织的完整性，刺激造血的恢复。恩托莫德刺激的IL-6产生对于恩托莫德拯救小鼠免于由与造血衰竭相关的5-FU剂量引起的死亡的能力是必不可少的。相比之下，IL-6诱导对于恩托莫德对药物损伤的胃肠道组织的保护和恢复不是必需的。在同基因小鼠CT 26结肠腺癌模型中，恩托莫德降低了5-FU的全身毒性，但没有降低其抗肿瘤功效，表明恩托莫德的保护作用对正常非肿瘤组织具有选择性。这些结果表明，恩托莫德具有通过减少其相关的造血和胃肠道毒性来拓宽遗传毒性抗癌药物的治疗窗的临床潜力。
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.