6-ketoprostaglandin-f1-alpha and Intestinal-Neoplasms

Epidemiologic and animal studies indicate that sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect against the incidence of colorectal neoplasia and subsequent mortality. We previously demonstrated that sulindac significantly reduces intestinal tumor load in Apc(Min/+)mice and the tumor regression was not necessarily correlated with prostaglandin biosynthesis. In the present study, we further investigate the relationship of NSAID treatment and tumorigenesis in the Apc(Min/+)mouse model. We demonstrate that indomethacin (9 ppm) is a very potent chemopreventive agent, reducing tumor load by 85% and significantly inhibiting basal and ex vivo prostaglandin formation (P< 0.006 and P< 0.0001, respectively). Aspirin (400 ppm) has a similar impact on reducing prostaglandin levels, but in contrast to indomethacin, is uneffective in reducing the tumor load. The data indicate a discordance between the impact of different NSAIDs on tumorigenesis in Apc(Min/+)mice.

Topics: 6-Ketoprostaglandin F1 alpha; Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arachidonic Acid; Aspirin; Body Weight; Dinoprostone; Eating; Indomethacin; Intestinal Mucosa; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Prostaglandin Antagonists

We showed previously that dietary eicosapentaenoic acid [EPA, 20:5(n-3)] is antitumorigenic in the APC:(Min/+) mouse, a genetic model of intestinal tumorigenesis. Only a few studies have evaluated the effects of dietary fatty acids, including EPA and docosahexaenoic acid [DHA, 22:6(n-3)], in this animal model and none have evaluated the previously touted antitumorigenicity of alpha-linolenic acid [ALA, 18:3(n-3)], conjugated linoleic acid [CLA, 77% 18:2(n-7)], or gamma-linolenic acid [GLA, 18:3(n-6)]. Stearidonic acid [SDA, 18:4(n-3)], the Delta6-desaturase product of ALA, which is readily metabolized to EPA, has not been evaluated previously for antitumorigenic efficacy. This study was undertaken to evaluate the antitumorigenicity of these dietary fatty acids (ALA, SDA, EPA, DHA, CLA and GLA) compared with oleic acid [OA, 18:1(n-9)] at a level of 3 g/100 g in the diets of APC:(Min/+) mice and to determine whether any alterations in tumorigenesis correspond to alterations in prostaglandin biosynthesis. Tumor multiplicity was significantly lower by approximately 50% in mice fed SDA or EPA compared with controls, whereas less pronounced effects were observed in mice fed DHA (P: = 0.15). ALA, CLA and GLA were ineffective at the dose tested. Although lower tumor numbers coincided with significantly lower prostaglandin levels in SDA- and EPA-fed mice, ALA and DHA supplementation resulted in equally low prostaglandin levels, despite proving less efficacious with regard to tumor number. Prostaglandin levels did not differ significantly in the CLA and GLA groups compared with controls. These results suggest that SDA and EPA attenuate tumorigenesis in this model and that this effect may be related in part to alterations in prostaglandin biosynthesis.

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Animals; Body Weight; Dietary Fats; Dinoprostone; Docosahexaenoic Acids; Eating; Fatty Acids; Fatty Acids, Omega-3; gamma-Linolenic Acid; Genes, APC; Intestinal Neoplasms; Intestines; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Phospholipids

In order to study the mechanism of cancer metastasis, AH100B cells, an ascitic hepatoma cell line, were transplanted into the small intestine of male Donryu rats. Each metastatic nodule in the liver was collected with the respective intestinal lesion. Each sample thus obtained was injected into the peritoneal cavity of male Donryu rats to make free cancer cells. Then, the cancer cells, having an intact cell surface, of the metastatic and primary intestinal lesion were collected respectively. After washing in Dolbecco's PBS (Ca2+ and Mg(2+)-free, pH 7.2), the definite numbers of cancer cells of the metastatic and primary intestinal lesion were incubated in the PBS containing [1-14C]-AA at 25 degrees C for 30 min, respectively. AA metabolites formed during the incubation period were extracted and subjected to TLC, followed by autoradiography. Each radioactive part was scraped off the plate and measured for its radioactivity. The pattern of the ability to synthesize PGs was different between the cancer cells which metastasized to the liver and those of the primary lesion, that is, percentage values of PGE2 and PGF2 alpha were higher (p < 0.01) in the cancer cells which metastasized to liver as compared with those of the primary intestinal lesion. These results suggest that PGs produced by hepatic metastatic cancer cells might play an important role in cancer metastasis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Carcinoma, Hepatocellular; Cell Line; Dinoprost; Dinoprostone; Intestinal Neoplasms; Liver Neoplasms; Male; Prostaglandin D2; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2; Tumor Cells, Cultured