Role of p53 in irinotecan-induced intestinal cell death and mucosal damage
Date
2007
Authors
Bowen, J.
Gibson, R.
Stringer, A.
Chan, T.
Prabowo, A.
Cummins, A.
Keefe, D.
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Advisors
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Journal article
Citation
Anti-Cancer Drugs, 2007; 18(2):197-210
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Bowen, Joanne M.; Gibson, Rachel J.; Stringer, Andrea M.; Chan, Thong W.; Prabowo, Avanita S.; Cummins, Adrian G.; Keefe, Dorothy M.K.
Conference Name
Abstract
Irinotecan treatment of colorectal cancers results inhigh-grade intestinal mucositis in a large proportion ofpatients. The mechanisms behind irinotecan-inducedmucosal injury, however, have yet to be fully explained. Theaim of this study was to investigate the role of the p53protein in the onset of intestinal damage followingirinotecan treatment in two different settings. IEC-6 andFHs 74 intestinal cell lines were treated with irinotecan withand without a temporary p53 inhibitor, pifithrin-a, andexamined for changes in proliferation and survivalalong with expression of p53 and related proteins. Fortytumour-bearing rats also underwent irinotecan treatmentwith and without pifithrin-a, and the effects onintestinal morphology, gene expression, apoptosis andother toxicities were assessed. Irinotecan caused adose-dependent reduction in cell viability that was notprevented by pifithrin-a in either cell line. Rats respondedto irinotecan with diarrhoea, weight loss, histopathologicalchanges to the small and large intestine, increased cryptapoptosis, and a mild inflammatory response. Pifithrin-areduced severity and duration of intestinal apoptosis;however, it did not significantly affect other parametersincluding p53 expression. Temporary inhibition of p53activation does not markedly prevent intestinal cell deathor mucositis following irinotecan treatment. Irinotecan mayact through upregulation of proapoptotic proteins Bax andBak to induce cell death.
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Copyright © 2007 Lippincott Williams & Wilkins, Inc.
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Copyright 2007 Lippincott Williams & Wilkins