Research Project
10262912
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.
