Identification of the mechanisms of 5-fluorouracil (5-FU)-induced Gastrointestinal (GI) toxicity in human colon

One of the major complications during pharmacological treatment of patients is the occurrence of adverse drug reactions (ADRs), for which the most affected organs are the liver, kidney, heart and the gastrointestinal-immune system. In comparison to the other organs, less progress has been made on human‐relevant prediction of drug‐induced intestinal toxicity, and it is clear that large data gaps are currently present. Therefore, new experimentation is required to assess GI toxicity by analyzing gene profile responses induced by exposure of GI system to different medicines. From a series of selected compounds, this study will specifically focus on 5-fluorouracil (5-FU)-induced intestinal toxicity. 5-FU was chosen as the first pharmaceutical to be studied in view of its wide use in cancer-therapy. The study will start by inclusion of metastatic breast cancer patients that will be receiving 5-FU as part of their medical treatment. These patients will receive an oral monotherapy consisting of cycles of two weeks treatment with capecitabine followed by one week without treatment. Capecitabine is a pro-drug that, after intake is converted into 5-FU, which is the actual cytostatic agent. After the first cycle, alterations in the physiology and morphology of colon biopsies will be evaluated, and 5-FU-induced transcriptomics signatures will be established through quantitative RNA sequencing. By doing so, we intend to obtain a better insight in the changes in the gene profile of biopsies caused by 5-FU as well as on its mechanism of action and toxicity. Eventually, we intend to compare this data with in vitro organoids and animal models and determine whether there is any relation or translatability between the models. The study can therefore be regarded as a validation study of potential in vitro and in vivo alternative models for studying drug induced GI-toxicity.

One of the major complications during pharmacological treatment of patients is the occurrence of adverse drug reactions (ADRs), for which the most affected organs are the liver, kidney, heart and the gastrointestinal-immune system. In comparison to the other organs, less progress has been made on human‐relevant prediction of drug‐induced intestinal toxicity, and it is clear that large data gaps are currently present. Therefore, new experimentation is required to assess GI toxicity by analyzing gene profile responses induced by exposure of GI system to different medicines. From a series of selected compounds, this study will specifically focus on 5-fluorouracil (5-FU)-induced intestinal toxicity. 5-FU was chosen as the first pharmaceutical to be studied in view of its wide use in cancer-therapy. Alterations in the physiology and morphology of colon biopsies are expected and will be evaluated, and 5-FU-induced transcriptomics signatures will be established through quantitative RNA sequencing. By doing so, we intend to obtain a better insight in the changes in the gene profile of biopsies caused by 5-FU as well as on its mechanism of action and toxicity.

One time before the start of the therapy and one time after 2 weeks of treatment.

Colonic biopsy tissues will be collected before and after the treatment, after the first cycle of chemotherapy is completed. Blood and faecal samples will also be collected at that time points.