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.

Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer.

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.

[Evaluation of syndrome X by exercise stress thallium-201 SPECT].

Using exercise stress thallium (Tl)-201 SPECT, we studied 11 patients with Syndrome X who had anginal pain and ischemic ECG change during exercise in spite of angiographically normal coronary artery. In three patients, the initial stress image showed mild hypoperfusion in the area of ST segment depression, but the delayed image showed complete or incomplete redistribution. Eight cases showed normal perfusion. This result suggests that some patients of Syndrome X could be caused by small vessel disease.