Towards better models and mechanistic biomarkers for drug-induced gastrointestinal injury

A Citrulline‐Based Translational Population System Toxicology Model for Gastrointestinal‐Related Adverse Events Associated With Anticancer Treatments

“…This finding is also supported by the literature from other groups where plasma citrulline appeared to correlate well the with histopathology findings in rats 14 and dogs. 6 A few important features were observed using plasma citrulline as a TD biomarker that could not be quantitatively captured by categorical histopathology scores: (i) the overshoot recovery, which was consistent with the reported overshoot recovery of villous cells after cytosine arabinoside treatment in mice 30 and hyperplastic response of the small bowel after partial intestinal resection in rats, 31 although the molecular mechanism has not been fully elucidated; (ii) more than concentration-proportional cytotoxic effects after irinotecan treatment in rats ( Figure 3); and (iii) the tolerance development observed after multiple doses, which was not tested previously by Shankaran et al (Figure S4). These features were successfully captured by the model advancements as described in the Materials and Methods section in detail.…”

“…No quantitative and translatable in vitro GI toxicity model is available beyond qualitative screening. 6 Irinotecan (CPT-11) is a camptothecin derivative that is widely used in the treatment of colorectal, pancreatic, and lung cancers. It is commonly used to study chemotherapy-induced GI toxicity as it is known to induce dose-limiting GI AEs in the clinic.…”

“…From the preclinical studies, dose-dependent decrease of plasma citrulline was observed and correlated well with GI toxicity observations in rats and dogs. 6,14 In the clinic, plasma citrulline has been used to monitor intestinal mucositis after chemotherapy and radiation therapy for cancer. 15,16 A normal adult has a mean citrulline plasma concentration of 40 μM.…”

Developingin vitroassays to transform gastrointestinal safety assessment: potential for microphysiological systems

“…For many clinicians, the best biomarker of GIT is still diarrhoea (or bloody diarrhoea indicating colitis) (reviewed in ref. 87). As an example of the expected impact, the cleaved ectodomain of KIM1 has emerged as a circulating biomarker of renal proximal tubule injury and is widely used to facilitate the early diagnosis of renal toxicity/disease.…”

“…Although diarrhoea has been considered the best indicator for GIT, it gives little to no information on the underlying mechanism or the target cells for toxicity. 87 Thus, a challenge for intestinal MPS models will be to reveal mechanistic insights of DI-GIT with histology, cell type analysis, or similar high-content tissue-level data. Mechanistic insight at the molecular level is equally important as this enables preclinical to clinical translation assessment.…”