Optimized rat models better mimic patients with irinotecan-induced severe diarrhea

Abstract

Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan’s application but also significantly affects patients’ quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors’ impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.

Keywords:

• Irinotecan
• severe diarrhea
• disease model
• gut toxicity
• reproducible

Ethical approval

Not applicable.

Author contributions

Zicong Zheng and Ting Du: experiment execution, sample analysis, data visualization, writing – original draft, review and editing; Song Gao, Taijun Yin, and Li Li: experiment execution, writing – original draft, review and editing; Lijun Zhu and Rashim Singh: review and editing; Rongjin Sun: conception and design of the study, experiment execution, sample analysis, writing – original draft, review and editing; Ming Hu: conception and design of the study, supervision, writing – review and editing, funding support.

Disclosure statement

The authors declare that they have no competing interests. Dr. Ming Hu and Dr. Rashim are the co-founders of Sanarentero LLC. Sanarentero is not involved in deciding the research direction of this project.

Data availability statement

The authors declare that all the data supporting the findings of this study are contained within the paper.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81961128028), National Cancer Institute (5R01CA246209), National Institute of General Medical Sciences (1R15GM126475-01A1), National Center for Complementary and Integrative Health (1R43AT011165-01A1), Cancer Prevention Research Institute of Texas (CPRIT) (RP190672), and Natural Science Foundation of Hubei Province of China (2021CFB247).