重组人白介素1受体拮抗剂预防化疗相关性腹泻的药理机制研究

Chemotherapy induced diarrhea (CID) is a common dose-limiting toxicity of cancer treatment. CID significantly affects the completion of chemotherapy and quality of life of cancer patients, in severe cases leads patients to shock or even death. There is no effective treatment to prevent CID, current drugs manage mild diarrhea by inhibiting bowel movements, which can not protect intestinal stem cells and progenitor cells, thus can not fundamently alleviate chemotherapy injury on intestinal mucose. Our previous work has demonstrated that recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) pretreatment before chemotherapy reduces the incidence and severity of CID in mice. rhIL-1Ra inhibits the proliferation of intestinal epithelial cells, thereby reduces their sensitivity to chemotherapy drugs, and alleviates chemotherapy injury on intestinal mucose. Using the clinical related tumor-bearing mice chemotherapy model, this project will focus on the study of pharmacodynamic and pharmacological mechanisms of rhIL-1Ra in the prevention of CID. Our goal is to identify the target cells for rhIL-1Ra during the regeneration of intestinal mucosa; to characterize the target genes of rhIL-1Ra in the regulation of intestinal epithelial cell cycle and signaling pathway involved. Our study will provide conclusive evidence of rhIL-1Ra in preventing CID, and at the same time not afftecting the therapeutical effect of chemotherapy on tumors. Through the years, our laboratory has built up a strong research background, valuable resources and working condition for the study of IL-1Ra and CID, providing reliable foundation to a successful completion of the project.

化疗相关性腹泻（CID）是肿瘤化疗常见剂量限制性毒性反应，严重时可导致病人休克甚至死亡。目前临床尚无预防CID的药物，已有治疗性药物通过抑制肠蠕动仅对轻度CID症状有缓解作用，不能从根本上预防化疗对肠黏膜上皮细胞的损伤。我们前期工作证实：化疗前应用重组人白介素1受体拮抗剂（rhIL-1Ra），显著降低小鼠CID发生率和严重程度。rhIL-1Ra通过抑制肠黏膜上皮细胞增殖，降低上皮细胞化疗敏感性，从而起到保护肠黏膜、预防CID的作用。本项目基于贴近临床的荷瘤小鼠化疗模型，开展IL-1Ra预防CID的药效药理机制研究，揭示IL-1Ra保护肠黏膜上皮作用的靶细胞；重点探究IL-1Ra调控肠黏膜细胞细胞周期的分子机制，明确关键效应因子和相关信号通路；最终确证IL-1Ra既能预防CID又不影响肿瘤化疗疗效及肿瘤生长。本课题组在IL-1Ra与CID方面有完善的研究基础和工作条件，为项目完成奠定坚实基础

化疗相关性腹泻（CID）是肿瘤化疗常见剂量限制性毒性反应，严重时可导致病人休克甚至死亡。目前临床尚无预防CID的药物，已有治疗性药物通过抑制肠蠕动仅对轻度CID症状有缓解作用，不能从根本上预防化疗对肠黏膜上皮细胞的损伤。本基金项目研究表明，重组人IL-1Ra（rhIL-1Ra）的使用能有效减轻5-FU 导致的肠黏膜损伤程度，大大降低腹泻发生率、严重程度和缩短腹泻持续时间，减轻体重降低和加速体重恢复，并且显著地提高了小鼠存活率。通过时效、量效和给药途径实验，我们确定rhIL-1Ra 的最适给药方案为化疗前连续5 天，每天一次，皮下注射，剂量为2 - 3 mg/kg。此外，阳性对照药实验、奥沙利铂（L-OHP）单药和L-OHP 联合5-FU 化疗等实验研究，验证了IL-1Ra 的CID 防治效果。我们还进一步验证了rhIL-1Ra 对荷瘤小鼠CID的防治效果，并确证rhIL-1Ra 不降低化疗对肿瘤的杀伤疗效。. 本基金项目还通过体内和体外实验深入研究了IL-1Ra 防治CID 的药理机制。结果表明外源性IL-1Ra，通过与IL-1RI 结合阻断IL-1 下游信号通路转导，选择性上调肠黏膜隐窝上皮细胞，而非肿瘤细胞p21WAF1 和p27KIP1的表达水平，从而使快速增殖的肠黏膜隐窝上皮细胞暂时脱离细胞周期。这种细胞周期阻滞作用改变了肠黏膜隐窝上皮细胞的状态，从而降低了其对化疗药物的敏感性，最终肠黏膜损伤减轻，并且更多残存的隐窝上皮细胞能加速化疗后肠黏膜的恢复。. 本基金项目证实了rhIL-1Ra 的高安全性和对CID 全面的、稳定的防治疗效，为临床CID 的防治提供了新的预防策略，也为rhIL-1Ra开发成预防CID的一类新药奠定坚实的临床前研究基础。