Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities

摘要 伊立替康是SN-38的前药，用于治疗多种类型的转移性和耐药癌症，通常 代表了最后一招的疗法。不幸的是，这些患者中有很大一部分(高达40%)将 经历严重(2级)和严重(3-4级)延迟性腹泻(SDOD)，这确实降低了级别 患者的生活质量。在某些情况下，SDOD可能会导致延长住院时间，甚至死亡。这个 我们研究的长期目标是开发实验性疗法和/或营养补充方法。 以减少SDOD，这样患者就可以继续进行化疗。我们最近的研究表明，灭活 SN-38对肠道UDP-葡萄糖醛酸基转移酶(UGTS)的作用是SN-38致病的新机制 而中药小柴胡汤(XCHT)可减轻小鼠脑组织中HSP70的失活 小鼠肠道UGT。因此，当前提案的中心假设是，因此，我们假设 XCHT将通过减弱UGT活性的下降，减少伊立替康诱导的SDOD，从而预防或减少伊立替康诱导的SDOD 肠道SN-38暴露，促进肠道UGT活性恢复。我们计划用四个实验来检验这一假设 具体目标：(1)进行XCHT的植物化学、生物制药和药代动力学表征 支持质量控制、全身和肠道药物暴露测定，并提供生物分析 临床研究和PK/PD模型所需的方法和药代动力学参数；(2)验证血浆 以雷洛昔芬-4‘-葡萄糖醛酸苷水平作为肠道UGT/UGT活性变化的探针； 支持人体机械性试验并确定XCHT抗肿瘤作用机制的研究 使用体外和体内模型进行伊立替康诱导的SDOD；以及(4)使用 一项安全“磨合”的随机双盲设计，以确定XCHT是否可以弱化人体肠道 UGT减少和降低伊立替康化疗引起的3级或更高程度腹泻的发生率。搁置一边 根据这些初步结果，我们还将确定肠道UGT活动的探针al-4‘-G的水平是否 与全身炎症细胞因子水平呈负相关。通过这项研究取得的成功将 为我们靶向治疗伊立替康化疗所致的SDOD提供了新的机制。

Abstract Irinotecan, a prodrug of SN-38, is used to treat many types of metastatic and drug-resistant cancers, and often represents the therapy of the last resort. Unfortunately, a large percentage (up to 40%) of these patients will experience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD), which really downgrade patient’s quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. The long-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approach to reduce SDOD, so patients can sustain their chemotherapy. Our recent studies have shown that inactivation of intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causes SDOD, and that a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (XCHT), could attenuate the inactivation of intestinal UGTs in mice. Therefore, the central hypothesis of this current proposal is Therefore, we hypothesize that XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities, reducing gut SN-38 exposure, and promoting the recovery of gut UGT activities. We plan to test this hypothesis using four Specific Aims: (1) perform phytochemical, biopharmaceutical and pharmacokinetic characterization of XCHT to enable quality control, systemic and intestinal drug exposure determinations, and to provide bioanalytical methods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasma raloxifene-4′-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse “co- trial” studies to support human mechanistic trials and to determine the mechanisms of action of XCHT against irinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial using a randomized double-blind design with a safety “Run-In” to determine if XCHT can attenuate human intestinal UGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Aside from these primary outcomes, we will also determine if levels of Ral-4’-G, a probe of intestinal UGT activities is (negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research will provide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy.