p21(WAF1/cip1) is an important determinant of intestinal cell response to sulindac in vitro and in vivo.
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/.
Yang
W
W
Department of Oncology, Albert Einstein Cancer Center, Bronx, New York 10467, USA.
Velcich
A
A
Mariadason
J
J
Nicholas
C
C
Corner
G
G
Houston
M
M
Edelmann
W
W
Kucherlapati
R
R
Holt
P R
PR
Augenlicht
L H
LH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004386:Duodenum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D017491:Genes, APC; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012007:Rectum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013467:Sulindac / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D013467:Sulindac