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

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    Authors
    Pritchard, D M
    Potten, Christopher S
    Hickman, John A
    Affiliation
    Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, United Kingdom.
    Issue Date
    1998-12-01
    
    Metadata
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    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.
    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
    URI
    http://hdl.handle.net/10541/93017
    PubMed ID
    9850079
    Type
    Article
    Language
    en
    ISSN
    0008-5472
    Collections
    All Paterson Institute for Cancer Research

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