Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3−/−) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3−/−, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3−/−, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3−/−. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

These results suggest that simultaneous stimulation of EP2 and EP4 is necessary and sufficient to elicit the effect of PGE(2)on rat primary chondrocyte differentiation.

Previous studies have shown that prostaglandin E 2 (PGE 2 ) is involved in intestinal carcinogenesis through its binding to the PGE 2 receptor subtypes EP 1 and EP 4 and activation of downstream pathways. ONO-8711 and ONO-AE2-227, prostaglandin E receptor subtype EP 1 -and EP 4 -selective antagonists, respectively, are known to suppress formation of intestinal polyps in adenomatous polyposis coli gene-deficient mice. The present study was designed to investigate the combined effects of EP 1 and EP 4 antagonists on spontaneous polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal tumorigenesis. APC1309 mice were treated with 400 ppm of ONO-8711 alone, 400 ppm of ONO-AE2-227 alone or both in combination in the diet for 6 weeks. The mean area of polyps found in the intestine, calculated as the longer diameter × × × × the shorter diameter × × × × π π π π, was reduced by 12%, 43% (P < < < <0.01) and 56% (P < < < <0.01) of the mean control value (8.8 mm yclooxygenase (COX) is a rate-limiting enzyme in the synthesis of prostaglandins (PGs), which affect cell proliferation, tumor growth, apoptosis and immune responsiveness. Two COX enzyme isoforms, known as COX-1 and COX-2, have been identified. COX-1 is constitutively expressed while COX-2 is transiently inducible by various agents such as cytokines, growth factors, and hormones, then contributing to inflammation and abnormal cell proliferation.1) There is evidence to suggest that COX-2 is involved in carcinogenesis in various organs, including the colon. 2-5) A possible contribution of COX-1 to colon carcinogenesis has also been reported. Genetic disruption of the COX-1 gene, as well as the COX-2 gene, decreased the number of intestinal polyps by around 80% in Min mice.6) It should be noted that prostaglandin E 2 (PGE 2 ) levels are elevated in intestinal polyps, compared with surrounding normal tissue, and both COX-1 and COX-2 contributed to PGE 2 production. 6) Moreover, we recently demonstrated that mofezolac, a COX-1 selective inhibitor, suppressed the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACFs), putative preneoplastic lesions in F344 rats, and intestinal polyp development in mice with a truncated adenomatous polyposis coli (Apc) gene at codon 1309 (APC1309 mice), an animal model of human familial adenomatous polyposis.7) These findings point to a significant role for PGE 2 , produced by COX-1 and COX-2, in colon carcinogenesis.Previous studies demonstrated that PGE 2 exerts its biological actions through binding to four specific membrane receptor subtypes known as EP 1 , EP 2 , EP 3 and EP 4 . 8, 9) Genetic and pharmacological studies with specific inhibitors have suggested that EP 1 10) and EP 4 11) are important for carcinogenesis. For example, addition of 500 ppm ONO-8711 and 300 ppm ONO-AE2-227, targeting EP 1 and EP 4 , respectively, to basal diet of Min mice reduced the number of polyps by 44% and 31%, respectively. In addition, the numbers of AOM-induced colonic ACFs were also...

Strong magneto-optical enhancement in highly Ce-substituted iron garnet films prepared by sputtering J. Appl. Phys. 70, 7065 (1991); 10.1063/1.349786Strong magneto-optical enhancement in highly Ce-substituted iron garnet films by sputtering (abstract)This article describes the demonstration of magneto-optic channel waveguides in Ce-substituted yttrium iron garnet which has a very large Faraday rotation. The rib waveguides are successfully produced by employing a new etching technique, which is a reactive ion etching method using BCls gas. The nonreciprocal phase shift in the magneto-optic waveguides is measured by using a new improved measurement method. These waveguides exhibit the largest nonreciprocal phase shift ever reported of 21.1 rad/cm @=1.55 pm). 4877

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