p21(WAF1/cip1) is an important determinant of intestinal cell response to sulindac in vitro and in vivo.

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/.

• Authors: W Yang, A Velcich, J Mariadason, C Nicholas, G Corner, M Houston, W Edelmann, R Kucherlapati, P R Holt, L H Augenlicht
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 16 Pg. 6297-302 (Aug 15 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11507085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• CDKN1A protein, human
• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Sulindac

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (biosynthesis, genetics, physiology)
• Duodenum (cytology, drug effects, physiology)
• Female
• Gene Dosage
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing (drug effects, physiology)
• Genes, APC
• Humans
• Intestinal Mucosa (cytology, drug effects, physiology)
• Male
• Mice
• Oligonucleotide Array Sequence Analysis
• Precancerous Conditions (drug therapy, genetics, pathology)
• Rectum (cytology, drug effects, physiology)
• Sulindac (pharmacology)