title: An alternative theory of tissue specificity by tumor promotion of okadaic acid in glandular stomach of SD rats.
abstract: To challenge the theory of tissue specificity of tumor promoters, the biochemical and tumor promoting effects of okadaic acid (OA), a potent tumor promoter on mouse skin, were studied in the mucosa of rat glandular stomach. OA strongly inhibited protein phosphatases 1 and 2A, and increased 4-fold the phosphorylation of elongation factor 2 in vitro in the mucosa. Intubation of 10 micrograms (12.4 nmol) OA induced ornithine decarboxylase in the mucosa. Tumor promotion of OA was studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a two-stage carcinogenesis experiment. OA in drinking water, 10 micrograms (12.4 nmol) per rat per day from weeks 9-55 of the experiment, and 20 micrograms (24.8 nmol) from weeks 56-72, significantly enhanced development of the neoplastic changes in the glandular stomach (P < 0.05). The neoplastic changes included adenomatous hyperplasias and adenocarcinomas, both of which correspond to papillomas and carcinomas in a two-stage mouse skin carcinogenesis experiment. The percentages of neoplastic change-bearing rats of the groups treated with MNNG plus OA, MNNG alone or OA alone were 75.0, 46.4 and 0% respectively. OA enhanced tumorigenesis in the MNNG-initiated glandular stomach of rats through the same mechanisms of action as in mouse skin. The OA pathway mediated through inhibition of protein phosphatases 1 and 2A is applicable to various organs as a general mechanism of tumor promotion.
authors.affiliation: National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Suganuma
authors.forename: M
authors.initials: M
authors.lastname: Tatematsu
authors.forename: J
authors.initials: J
authors.lastname: Yatsunami
authors.forename: S
authors.initials: S
authors.lastname: Yoshizawa
authors.forename: S
authors.initials: S
authors.lastname: Okabe
authors.forename: D
authors.initials: D
authors.lastname: Uemura
authors.forename: H
authors.initials: H
authors.lastname: Fujiki
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D004790:Enzyme Induction; D004988:Ethers, Cyclic / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology; D008297:Male; D008769:Methylnitronitrosoguanidine; D019319:Okadaic Acid; D009928:Organ Specificity; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects* / Q000201:enzymology; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000201:enzymology
chemical_list: D002273:Carcinogens; D004988:Ethers, Cyclic; D008769:Methylnitronitrosoguanidine; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D009955:Ornithine Decarboxylase