Irinotecan-induced Mucositis Manifesting As Diarrhoea Corresponds with an Amended Intestinal Flora and Mucin Profile

Overview

Journal Int J Exp Pathol

Publisher Wiley

Specialty Pathology

Date 2009 Sep 22

PMID 19765103

Citations 54

Authors

Andrea M Stringer

Rachel J Gibson

Joanne M Bowen

Richard M Logan

Kimberly Ashton

Ann S J Yeoh

Noor Al-Dasooqi

Dorothy M K Keefe

Affiliations

Soon will be listed here.

Abstract

Chemotherapy-induced diarrhoea is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. Irinotecan is linked with severe mucositis and diarrhoea, the mechanisms of which remain poorly understood. Bacterial beta-glucuronidase is thought to be involved in the metabolism of irinotecan, implicating the intestinal flora. Intestinal mucins may also be implicated in the development of chemotherapy-induced diarrhoea. Rats were treated with 200 mg/kg of irinotecan and killed at 96, 120 and 144 h. The rats were monitored for diarrhoea. Pathology and immunohistochemical staining was performed. The samples were cultured and faecal DNA was analysed using real-time polymerase chain reaction. Severe diarrhoea was observed from 72 to 96 h. A decrease in body mass was also observed after treatment. Significant changes in goblet cell numbers (both complete and cavitated cells) were observed in the small and large intestines. Changes in MUC gene expression were observed in the small intestine only. Modifications were observed to the intestinal flora profile, especially Escherichia coli, and an increase in the expression of beta-glucuronidase was detected. In conclusion, irinotecan-induced diarrhoea may be caused by an increase in some beta-glucuronidase-producing bacteria, especially E. coli, exacerbating the toxicity of active metabolites. Accelerated mucous secretion and mucin release may also contribute to the delayed onset of diarrhoea.

Citing Articles

Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation.

Chen M, Li Y, Chen P J Mol Histol. 2025; 56(2):101.

PMID: 40056250 PMC: 11890403. DOI: 10.1007/s10735-025-10367-w.

Crosstalk between gut microbiota and cancer chemotherapy: current status and trends.

Yang S, Hao S, Ye H, Zhang X Discov Oncol. 2024; 15(1):833.

PMID: 39715958 PMC: 11666878. DOI: 10.1007/s12672-024-01704-8.

The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review.

Hillege L, Stevens M, Kristen P, de Vos-Geelen J, Penders J, Redinbo M J Cancer Res Clin Oncol. 2024; 150(11):495.

PMID: 39537966 PMC: 11561038. DOI: 10.1007/s00432-024-06028-2.

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

Zheng Z, Du T, Gao S, Yin T, Li L, Zhu L Toxicol Mech Methods. 2024; 34(5):572-583.

PMID: 38390772 PMC: 11095999. DOI: 10.1080/15376516.2024.2316003.

Prediction of gastrointestinal symptoms trajectories using omega-3 and inflammatory biomarkers in early-stage breast cancer patients receiving chemotherapy.

Arcos D, Ng D, Ke Y, Toh Y, Chan A Support Care Cancer. 2024; 32(1):76.

PMID: 38170327 PMC: 10764400. DOI: 10.1007/s00520-023-08274-5.

References

Araki E, Ishikawa M, Iigo M, Koide T, Itabashi M, Hoshi A . Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res. 1993; 84(6):697-702. PMC: 5919320. DOI: 10.1111/j.1349-7006.1993.tb02031.x. View

Rinttila T, Kassinen A, Malinen E, Krogius L, Palva A . Development of an extensive set of 16S rDNA-targeted primers for quantification of pathogenic and indigenous bacteria in faecal samples by real-time PCR. J Appl Microbiol. 2004; 97(6):1166-77. DOI: 10.1111/j.1365-2672.2004.02409.x. View

Barcelo A, Claustre J, Moro F, Chayvialle J, Cuber J, Plaisancie P . Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut. 2000; 46(2):218-24. PMC: 1727811. DOI: 10.1136/gut.46.2.218. View

Quigley E . Probiotics in the management of colonic disorders. Curr Gastroenterol Rep. 2007; 9(5):434-40. DOI: 10.1007/s11894-007-0055-7. View

Logan R, Gibson R, Bowen J, Stringer A, Sonis S, Keefe D . Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol. 2007; 62(1):33-41. DOI: 10.1007/s00280-007-0570-0. View

Stringer A, Gibson R, Logan R, Bowen J, Yeoh A, Burns J . Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat. Exp Biol Med (Maywood). 2007; 232(1):96-106. View

Stringer A, Gibson R, Logan R, Bowen J, Yeoh A, Keefe D . Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats. Cancer Biol Ther. 2008; 7(12):1919-25. DOI: 10.4161/cbt.7.12.6940. View

Brandi G, Dabard J, Raibaud P, Di Battista M, Bridonneau C, Pisi A . Intestinal microflora and digestive toxicity of irinotecan in mice. Clin Cancer Res. 2006; 12(4):1299-307. DOI: 10.1158/1078-0432.CCR-05-0750. View

Elting L, Cooksley C, Chambers M, Garden A . Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys. 2007; 68(4):1110-20. DOI: 10.1016/j.ijrobp.2007.01.053. View

10.

Evaldson G, Heimdahl A, Kager L, Nord C . The normal human anaerobic microflora. Scand J Infect Dis Suppl. 1982; 35:9-15. View

11.

Smith N, Figg W, Sparreboom A . Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro. 2005; 20(2):163-75. DOI: 10.1016/j.tiv.2005.06.045. View

12.

Penders J, Vink C, Driessen C, London N, Thijs C, Stobberingh E . Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol Lett. 2005; 243(1):141-7. DOI: 10.1016/j.femsle.2004.11.052. View

13.

Bowen J, Stringer A, Gibson R, Yeoh A, Hannam S, Keefe D . VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss. Cancer Biol Ther. 2007; 6(9):1449-54. DOI: 10.4161/cbt.6.9.4622. View

14.

Gibson R, Bowen J, Keefe D . Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats. Int J Cancer. 2005; 116(3):464-70. DOI: 10.1002/ijc.21082. View

15.

Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E . Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 1996; 56(16):3752-7. View

16.

Layton A, McKay L, Williams D, Garrett V, Gentry R, Sayler G . Development of Bacteroides 16S rRNA gene TaqMan-based real-time PCR assays for estimation of total, human, and bovine fecal pollution in water. Appl Environ Microbiol. 2006; 72(6):4214-24. PMC: 1489674. DOI: 10.1128/AEM.01036-05. View

17.

Ikuno N, Soda H, Watanabe M, Oka M . Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J Natl Cancer Inst. 1995; 87(24):1876-83. DOI: 10.1093/jnci/87.24.1876. View

18.

Takasuna K, Hagiwara T, Watanabe K, Onose S, Yoshida S, Kumazawa E . Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea. Cancer Chemother Pharmacol. 2006; 58(4):494-503. DOI: 10.1007/s00280-006-0187-8. View

19.

Tryland I, Fiksdal L . Enzyme characteristics of beta-D-galactosidase- and beta-D-glucuronidase-positive bacteria and their interference in rapid methods for detection of waterborne coliforms and Escherichia coli. Appl Environ Microbiol. 1998; 64(3):1018-23. PMC: 106360. DOI: 10.1128/AEM.64.3.1018-1023.1998. View

20.

Logan R, Stringer A, Bowen J, Yeoh A, Gibson R, Sonis S . The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev. 2007; 33(5):448-60. DOI: 10.1016/j.ctrv.2007.03.001. View