Biomaterial Database

Inhibition of two-stage skin carcinogenesis as well as complete skin carcinogenesis by oral administration of TMK688, a potent lipoxygenase inhibitor. 1994

H Jiang, and S Yamamoto, and R Kato

Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.

1-([5'-(3''-methoxy-4''-ethoxycarbonyloxyphenyl)-2',4'- pentadienoyl]aminoethyl)-4-diphenylmethoxypiperidine (TMK688) is a potent and orally active 5-lipoxygenase inhibitor having anti-histamine activity in its moiety. Recently, we have found that TMK688 also inhibits epidermal cyclooxygenase activity with a potency similar to its inhibiting 5-lipoxygenase. Oral administration of 30 mg/kg TMK688, a dose which markedly inhibits tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated LTB4 formation in mouse skin, markedly inhibited both TPA-promoted and a non-TPA-type tumor promoter anthralin-promoted skin tumor formation in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated CD-1 mice. The inhibitory effect of TMK688 was not due to any damage inflicted on the initiated cells but due to its antitumor-promoting activity. TMK688 not only inhibited two-stage skin carcinogenesis but also inhibited benzo[a]pyrene-caused complete skin carcinogenesis. Throughout the tumorigenesis experiment, the survival rate of animals was 100% and the TMK688-treated mice looked healthy. The body weight gain of TMK688-treated mice was not significantly different from that of non-treated mice. Both TMK688 and 1-([5'-(3''-methoxy-4''-hydroxyphenyl)-2',4'-pentadienoyl]amino eth yl]-4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688 having more potent 5-lipoxygenase inhibitory activity and less potent cyclooxygenase inhibitory activity than TMK688, inhibited epidermal 8-lipoxygenase activity induced by a topical application of TPA to mouse skin. The 8-lipoxygenase inhibitory activity of TMK777 was approximately 5 times more potent than that of TMK688. Indomethacin, a typical cylcloxygenase inhibitor, in topical doses which almost completely inhibit epidermal PGE2 formation, failed to inhibit or only slightly inhibited DMBA-initiated and TPA-promoted skin tumor formation. These results suggest that the cyclooxygenase inhibitory effect of TMK688 is not essential for its anti-tumor promoting activity. Although at present a possible contribution of anti-histamine activity cannot be ruled out completely, the anti-tumor promoting action of TMK688 may most probably be related to its anti-lipoxygenase activity. TMK688 seems to be a promising agent for the prevention of skin carcinogenesis.

UI	MeSH Term	Description	Entries
D007213	Indomethacin	A non-steroidal anti-inflammatory agent (NSAID) that inhibits CYCLOOXYGENASE, which is necessary for the formation of PROSTAGLANDINS and other AUTACOIDS. It also inhibits the motility of POLYMORPHONUCLEAR LEUKOCYTES.	Amuno,Indocid,Indocin,Indomet 140,Indometacin,Indomethacin Hydrochloride,Metindol,Osmosin
D008815	Mice, Inbred Strains	Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations, or by parent x offspring matings carried out with certain restrictions. All animals within an inbred strain trace back to a common ancestor in the twentieth generation.	Inbred Mouse Strains,Inbred Strain of Mice,Inbred Strain of Mouse,Inbred Strains of Mice,Mouse, Inbred Strain,Inbred Mouse Strain,Mouse Inbred Strain,Mouse Inbred Strains,Mouse Strain, Inbred,Mouse Strains, Inbred,Strain, Inbred Mouse,Strains, Inbred Mouse
D010880	Piperidines	A family of hexahydropyridines.
D005260	Female		Females
D000284	Administration, Oral	The giving of drugs, chemicals, or other substances by mouth.	Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000287	Administration, Topical	The application of drug preparations to the surfaces of the body, especially the skin (ADMINISTRATION, CUTANEOUS) or mucous membranes. This method of treatment is used to avoid systemic side effects when high doses are required at a localized area or as an alternative systemic administration route, to avoid hepatic processing for example.	Drug Administration, Topical,Administration, Topical Drug,Topical Administration,Topical Drug Administration,Administrations, Topical,Administrations, Topical Drug,Drug Administrations, Topical,Topical Administrations,Topical Drug Administrations
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001091	Arachidonate Lipoxygenases	Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates. These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids. The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- .	Arachidonic Acid Lipoxygenase,Lipoxygenase, Arachidonic Acid,Lipoxygenases, Arachidonate
D001564	Benzo(a)pyrene	A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component of tobacco smoke.	3,4-Benzopyrene,3,4-Benzpyrene,3,4 Benzopyrene,3,4 Benzpyrene
D012867	Skin	The outer covering of the body that protects it from the environment. It is composed of the DERMIS and the EPIDERMIS.