Piroxicam-induced regression of intestinal adenomatous polyps in APC(delta474) mice.
Mutation of adenomatous polyposis coli (APC) gene results in incidence or development of polyps and colorectal cancer. It has been reported that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cell growth, cause cell cycle arrest, and induce apoptosis. The aims of this study are to investigate chemopreventive effects of piroxicam and elucidate its mechanism. All APC(delta474) mice have intestinal polyps. Thirty-five APC(delta474) mice were divided into three groups: 0.005% solution of piroxicam in tap water was given for P group (n = 15) and 0.001% solution for P' group (n = 5), and water without piroxicam for C group (n = 15) from 4 weeks of age to 12 weeks, respectively. All mice were sacrificed at the 12th week after birth. Hematoxylin-eosin staining for number and size of polyps, immunohistochemical staining for cyclooxygenase (COX)-1 and -2, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), TUNEL method, and Western blot analysis of COX-2 and VEGF were performed. Polyps were divided into two types of large polyps of >or=300 microm in diameter and small polyps of <300 microm. The number of large polyps in P group decreased significantly compared with C group (p <.0001), but without significant difference in small polyps. There were no significant differences in PCNA index in both of large and small polyps among the three groups. Apoptotic index of polyps in P group increased more than those in C group (p <.05). There was immunohistochemically no significant difference in COX-1 positivity of normal intestinal epithelia and adenomas among three groups. Both numbers of VEGF-positive cells and COX-2 positive cells in the stroma of the small intestine were significantly downregulated in P group (p <.05). COX-2 expression was inhibited in dose-dependent manner without significant difference. There were no significant differences in VEGF expression between P' and C groups. In conclusion, piroxicam suppressed the development of large polyps in APC(delta474) mice by inducing apoptosis and inhibiting VEGF expression in interstitial cells of polyps.
Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Z F
ZF
Qiu
K
K
Maruyama
K
K
Sunayama
H
H
Kashiwabara
T
T
Shoji
T
T
Nakamura
S
S
Suzuki
H
H
Konno
S
S
Nakamura
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D017491:Genes, APC; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010894:Piroxicam / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D010894:Piroxicam; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse