The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia.

2.50
Hdl Handle:
http://hdl.handle.net/10541/93017
Title:
The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia.
Authors:
Pritchard, D M; Potten, Christopher S; Hickman, John A
Abstract:
The relationship between acute (<36 h) induction of apoptosis and longer-term (>72 h) intestinal histopathology was systematically investigated in vivo using p53 wild-type (+/+) and null (-/-) mice. Administration of the enterotoxin 5-fluorouracil (5-FU) at either 40 or 400 mg/kg to BDF1 mice induced an acute p53-dependent apoptosis in the crypts of both small intestine and midcolon. Although the amount of apoptosis was of the same order of magnitude at its peak (24 h) at both doses, only 400 mg/kg 5-FU brought about histopathological changes to the gut after 96 h, quantified as losses of crypt and villus cellularity. Only after the administration of 400 mg/kg 5-FU were mitotic index and DNA synthesis significantly suppressed in both small intestinal and midcolonic crypts at 24 h. This correlated with a prolonged, p53-dependent expression of p21waf-1/cip1. In p53 null (-/-) mice, significant reductions in both 5-FU-induced apoptosis and inhibition of cell cycle progression allowed retention of crypt integrity 96 h after 5-FU. These results show that quantitative measures of acute apoptosis in vivo may not accurately predict subsequent pathological changes in the gut. Rather, p53-dependent inhibition of cell cycle progression, together with cell loss by apoptosis, caused a loss of crypt integrity. Importantly, the tissue toxicity of 5-FU was genetically determined at a locus (p53) separate from that directly associated with drug action.
Affiliation:
Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, United Kingdom.
Citation:
The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia. 1998, 58 (23):5453-65 Cancer Res.
Journal:
Cancer Research
Issue Date:
1-Dec-1998
URI:
http://hdl.handle.net/10541/93017
PubMed ID:
9850079
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPritchard, D Men
dc.contributor.authorPotten, Christopher Sen
dc.contributor.authorHickman, John Aen
dc.date.accessioned2010-02-25T10:50:14Z-
dc.date.available2010-02-25T10:50:14Z-
dc.date.issued1998-12-01-
dc.identifier.citationThe relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia. 1998, 58 (23):5453-65 Cancer Res.en
dc.identifier.issn0008-5472-
dc.identifier.pmid9850079-
dc.identifier.urihttp://hdl.handle.net/10541/93017-
dc.description.abstractThe relationship between acute (<36 h) induction of apoptosis and longer-term (>72 h) intestinal histopathology was systematically investigated in vivo using p53 wild-type (+/+) and null (-/-) mice. Administration of the enterotoxin 5-fluorouracil (5-FU) at either 40 or 400 mg/kg to BDF1 mice induced an acute p53-dependent apoptosis in the crypts of both small intestine and midcolon. Although the amount of apoptosis was of the same order of magnitude at its peak (24 h) at both doses, only 400 mg/kg 5-FU brought about histopathological changes to the gut after 96 h, quantified as losses of crypt and villus cellularity. Only after the administration of 400 mg/kg 5-FU were mitotic index and DNA synthesis significantly suppressed in both small intestinal and midcolonic crypts at 24 h. This correlated with a prolonged, p53-dependent expression of p21waf-1/cip1. In p53 null (-/-) mice, significant reductions in both 5-FU-induced apoptosis and inhibition of cell cycle progression allowed retention of crypt integrity 96 h after 5-FU. These results show that quantitative measures of acute apoptosis in vivo may not accurately predict subsequent pathological changes in the gut. Rather, p53-dependent inhibition of cell cycle progression, together with cell loss by apoptosis, caused a loss of crypt integrity. Importantly, the tissue toxicity of 5-FU was genetically determined at a locus (p53) separate from that directly associated with drug action.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshAntimetabolites, Antineoplastic-
dc.subject.meshApoptosis-
dc.subject.meshCell Division-
dc.subject.meshColon-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p21-
dc.subject.meshCyclins-
dc.subject.meshDNA-
dc.subject.meshEpithelium-
dc.subject.meshFemale-
dc.subject.meshFluorouracil-
dc.subject.meshIntestine, Small-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Inbred DBA-
dc.subject.meshMitosis-
dc.subject.meshPrecancerous Conditions-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleThe relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, United Kingdom.en
dc.identifier.journalCancer Researchen

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