Abstract
Sulindac, a nonsteroidal anti-inflammatory drug, inhibits intestinal tumorigenesis in humans and rodents. Sulindac induced complex alterations in gene expression, but only 0.1% of 8063 sequences assayed were altered similarly by the drug in rectal biopsies of patients treated for 1 month and during response of colonic cells in culture. Among these changes was induction of the cyclin-dependent kinase inhibitor, p21(WAF1/cip1). In Apc1638(+/-) mice, targeted inactivation of p21 increased intestinal tumor formation in a gene-dose-dependent manner, but inactivation of p21 completely eliminated the ability of sulindac to both inhibit mitotic activity in the duodenal mucosa and to inhibit Apc-initiated tumor formation. Thus, p21 is essential for tumor inhibition by this drug. The array data can be accessed on the Internet at http://sequence.aecom.yu.edu/genome/.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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Cyclins / physiology*
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Duodenum / cytology
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Duodenum / drug effects
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Duodenum / physiology
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Female
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Gene Dosage
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Silencing / drug effects
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Gene Silencing / physiology
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Genes, APC
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Humans
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Intestinal Mucosa / cytology
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Intestinal Mucosa / drug effects*
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Intestinal Mucosa / physiology
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Male
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Mice
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Oligonucleotide Array Sequence Analysis
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Precancerous Conditions / drug therapy
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Precancerous Conditions / genetics
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Precancerous Conditions / pathology
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Rectum / cytology
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Rectum / drug effects
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Rectum / physiology
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Sulindac / pharmacology*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Sulindac