Establishment of a single-dose irinotecan model of gastrointestinal mucositis.
BACKGROUND
Irinotecan is a common cytotoxic agent used in advanced colorectal cancers. However, a major clinical problem with this cytotoxic is that it causes gastrointestinal mucositis manifest by severe diarrhoea. To date there is no established single dose of irinotecan in rats to enable determination of changes occurring following administration. Therefore, the primary aim of this study was to determine a single dose of irinotecan that induced reproducible gastrointestinal mucositis in DA rats. The secondary aim was to determine if the presence of tumour altered the development of mucositis.


METHODS
Eighty-eight rats were divided into two groups, 44 received tumours and 44 remained tumour naïve. These were randomized to receive a single dose of irinotecan at 150, 200, 250 or 300 mg/kg. Two control groups of rats received either no treatment or 2 doses of 150 mg/kg irinotecan, shown previously to induce reproducible gastrointestinal mucositis. Rats were monitored closely for incidence and severity of diarrhoea, and mortality, before being killed 48 and 144 h following treatment.


RESULTS
Rats administered 250 and 300 mg/kg of irinotecan all developed diarrhoea, and this was associated with high mortality rates (up to 100%). Necropsies revealed that many of these rats had duodenal perforations and fatty lysis consistent with peritonitis. The lower doses of 150 and 200 mg/kg irinotecan also caused diarrhoea, but were not associated with high mortality rates. Histopathological examination confirmed small and large intestinal damage in all rats that received irinotecan, regardless of dose. Tumour-bearing rats had worse diarrhoea and higher mortality compared to tumour-naïve rats.


CONCLUSIONS
We find that a single dose of 200 mg/kg irinotecan causes reproducible gastrointestinal mucositis as measured by levels of diarrhoea, and small and large intestinal histology. Importantly this dose has a low mortality. The response to irinotecan is more pronounced in tumour-bearing rats.
Gibson
Rachel J
RJ
Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, Australia. rachel.gibson@imvs.sa.gov.au
Bowen
Joanne M
JM
Alvarez
Enrique
E
Finnie
John
J
Keefe
Dorothy M K
DM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced; D004195:Disease Models, Animal; D005260:Female; D000077146:Irinotecan; D052016:Mucositis / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D015996:Survival Rate
D000077146:Irinotecan; D002166:Camptothecin