Scientists from Shanghai Institute of Materia Medica (SIMM) and Institute of Biochemistry and Cell Biology (IBCB), CAS, made progress in understanding the mechanism of chemotherapy caused intestinal toxicity, and found therapeutic solutions that may be applied for limiting the toxicity using clinically available drugs. The finding has been published advanced online in Cell Research.

Chemotherapies in cancer treatment often cause severe side effects due to their caused broad damage to both tumor cells and fast-growing healthy cells. Intestinal toxicity, mostly known as diarrhea, is a common side effect caused by different kinds of chemotherapy drugs, particularly irinotecan (CPT-11) and fluorouracil.

CPT-11 is the first-line treatment for colorectal cancer (CRC). It causes severe diarrhea in up to 40% of patients receiving this treatment. Such persistent or severe diarrhea is a life-threatening for CRC patients, and often the reason for discontinuation of therapy in clinical practice. Thus far, the mechanism of CPT-11-caused diarrhea is still poorly understood, leaving a big challenge to the clinical management of this side effect.

Researchers at the SIMM and IBCB discovered that CPT-11 caused fast-growing intestine cells releasing a kind of DNA fragment, also known as double-stranded DNA (dsDNA). dsDNA in the local environment of intestine is carried by exosome, a form of small membrane vesicles, to enter the cytosol of innate immune cells.

Intracellular dsDNA can activate the AIM2 (absent in melanoma 2) inflammasome, a multi-protein cytoplasmic complex responsible for activation of inflammatory processes. Local inflammation in intestine in turn, causes intestinal damage and severe diarrhea.

Importantly, the finding suggested a therapeutic solution that may be applied for reducing the CPT-11-associated intestinal toxicity using drugs already in clinical use.

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Science and Technology Major Project and grants from the Natural Science Foundation of China.