ArticleProceedings of the National Academy of Sciences of the United States of America2013
Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 116 citations in OpenAlex.
- Comparative Pharmacokinetics of Six Bioactive Constituents From Danggui Jixueteng Decoction in Normal and Myelosuppressive Rats.Analytical science advances · 2026Article
- Targeting FAR1 to inhibit intestinal macrophage ferroptosis: repurposing irinotecan as a novel sepsis therapy.Apoptosis : an international journal on programmed cell death · 2026Article
- Mechanistic PBPK/PD modeling of free and nano-liposomal irinotecan reveals formulation-specific determinants of disposition and efficacy.International journal of pharmaceutics · 2026Article
- Development of an adult whole-body PBPK model of irinotecan and its metabolites for predicting UGT1A1/CYP3A-mediated drug-drug interactions.Frontiers in pharmacology · 2026Article
- OATP2B1 Deficiency Ameliorates Irinotecan-Induced Gastrointestinal Toxicity.Clinical and translational science · 2026Article
- An abundant ginger compound furanodienone alleviates gut inflammation via the xenobiotic nuclear receptor PXR in mice.Nature communications · 2025Article
- Rifaximin alleviates irinotecan-induced diarrhea in mice model.Annals of medicine · 2024Article
- Fecal SN-38 Content as a Surrogate Predictor of Intestinal SN-38 Exposure and Associated Irinotecan-induced Severe Delayed-Onset Diarrhea by a Novel Use of the Spectrofluorimetric Method.Pharmaceutical research · 2024Article
- Discovery of Prenyltransferase-Guided Hydroxyphenylacetic Acid Derivatives from Marine FungusMarine drugs · 2024Article
- Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment.Journal of translational medicine · 2024Article
- Recent developments in natural biopolymer based drug delivery systems.RSC advances · 2023Review
- Opioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.British journal of pharmacology · 2023Article
- Gegen Qinlian standard decoction alleviated irinotecan-induced diarrhea via PI3K/AKT/NF-κB axis by network pharmacology prediction and experimental validation combination.Chinese medicine · 2023Article
- Green tea extract prevents CPT-11-induced diarrhea by regulating the gut microbiota.Scientific reports · 2023Article
- Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models.International journal of molecular sciences · 2022Article
- Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.Advanced healthcare materials · 2022Article
- Article
- Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome.International journal of molecular sciences · 2022Article
- Virtual Screening for the Discovery of Microbiome β-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity.Journal of chemical information and modeling · 2022Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(ΔHep)) and the intestine (Ugt1(ΔGI)). Control (Ugt1(F/F)), Ugt1(ΔHep), and Ugt1(ΔGI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(ΔHep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(ΔGI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.
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