Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis.
OBJECTIVE
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-kappaB (NF-kappaB), tumor necrosis factor (TNF) and interleukins-1beta (IL-1beta) 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-kappaB, TNF, IL-1beta 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-kappaB, TNF and IL-1beta 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-kappaB 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.
Logan
Richard M
RM
Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, SA 5005, Australia. richard.logan@adelaide.edu.au
Gibson
Rachel J
RJ
Bowen
Joanne M
JM
Stringer
Andrea M
AM
Sonis
Stephen T
ST
Keefe
Dorothy M K
DM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D003106:Colon / Q000473:pathology; D004396:Coloring Agents; D016207:Cytokines / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology; D004064:Digestive System / Q000473:pathology*; D004801:Eosine Yellowish-(YS); D005260:Female; D005456:Fluorescent Dyes; D005753:Gastric Mucosa / Q000473:pathology*; D006416:Hematoxylin; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology*; D000077146:Irinotecan; D007583:Jejunum / Q000473:pathology; D009061:Mouth Mucosa / Q000473:pathology*; D052016:Mucositis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats
D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D016207:Cytokines; D005456:Fluorescent Dyes; D016328:NF-kappa B; D000077146:Irinotecan; D004801:Eosine Yellowish-(YS); D002166:Camptothecin; D006416:Hematoxylin