Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

Bach, S P, Williamson, S E, O'Dwyer, S T, Potten, C S and Watson, A J M (2006) Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut. British Journal of Cancer, 95 (1). pp. 35-41. ISSN 0007-0920

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Abstract

Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (-/-) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg(-1)) or low (40 mg kg(-1)) dose 5-FU+/-250 mg kg(-1) PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.

Item Type: Article
Uncontrolled Keywords: animals,antioxidants,apoptosis,colorectal neoplasms,dose-response relationship, drug,drug administration schedule,drug antagonism,drug synergism,fluorouracil,intestinal mucosa,intestine, large,intestine, small,mice,mice, knockout,mitosis,organ specificity,pyrrolidines,thiocarbamates,time factors,tumor suppressor protein p53,xenograft model antitumor assays
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
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Depositing User: Rhiannon Harvey
Date Deposited: 14 Jul 2011 09:17
Last Modified: 25 Jul 2018 06:00
URI: https://ueaeprints.uea.ac.uk/id/eprint/33688
DOI: 10.1038/sj.bjc.6603224

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