Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis

• Published in: Cancer chemotherapy and pharmacology 2008-06, Vol.62 (1), p.33-41
• Main Authors: Logan, Richard M., Gibson, Rachel J., Bowen, Joanne M., Stringer, Andrea M., Sonis, Stephen T., Keefe, Dorothy M. K.
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - toxicity; Atrophy; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - toxicity; Cancer Research; Chemotherapy; Colon; Colon - pathology; Coloring Agents; Cytokines; Cytokines - metabolism; Diarrhea; Diarrhea - chemically induced; Diarrhea - pathology; Digestive System - pathology; Eosine Yellowish-(YS); Female; Fluorescent Dyes; Gastric Mucosa - pathology; Gastrointestinal tract; Hematoxylin; IL-1β; Immunohistochemistry; Inflammation; Interleukin 6; Intestinal Mucosa - pathology; Irinotecan; Jejunum; Jejunum - pathology; Medical sciences; Medicine; Medicine & Public Health; Mouth Mucosa - pathology; Mucosa; Mucositis; Mucositis - chemically induced; Mucositis - metabolism; Mucositis - pathology; NF-kappa B - metabolism; NF-κB protein; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Rats; Reduction; Small intestine; Transcription factors; Tumor necrosis factor; Tumor necrosis factor-TNF; Villus
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-007-0570-0

Purpose The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogenesis of mucositis. The aim of this study was to determine the expression of nuclear factor-κB (NF-κB), tumor necrosis factor (TNF) and interleukins-1β (IL-1β) and -6 (IL-6) in the AT following the administration of the chemotherapeutic agent irinotecan. Methods Eighty-one female dark Agouti rats were assigned to either control or experimental groups according to a specific time point. Following administration of irinotecan, rats were monitored for the development of diarrhoea. The rats were killed at times ranging from 30 min to 72 h after administration of irinotecan. Oral mucosa, jejunum and colon were collected and standard immunohistochemical techniques were used to identify NF-κB, TNF, IL-1β and IL-6 within the tissues. Sections were also stained with haematoxylin and eosin for histological examination. Results Irinotecan caused mild to moderate diarrhoea in a proportion of the rats that received the drug. Altered histological features of all tissues from rats administered irinotecan were observed which included epithelial atrophy in the oral mucosa, reduction of villus height and crypt length in the jejunum and a reduction in crypt length in the colon. Tissue staining for NF-κB, TNF and IL-1β and IL-6 peaked at between 2 and 12 h in the tissues examined. Conclusions This is the first study to demonstrate histological and immunohistochemical evidence of changes occurring concurrently in different sites of the AT following chemotherapy. The results of the study provide further evidence for the role of NF-κB and associated pro-inflammatory cytokines in the pathobiology of AT mucositis. The presence of these factors in tissues from different sites of the AT also suggests that there may be a common pathway along the entire AT causing mucositis following irinotecan administration.