Biomaterial Database

Inhibition of mouse skin tumor promotion and of promoter-stimulated epidermal polyamine biosynthesis by alpha-difluoromethylornithine. 1983

M Takigawa, and A K Verma, and R C Simsiman, and R K Boutwell

Application of the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin leads to a manifold induction of ornithine decarboxylase (ODC) activity within 5 hr and an increased accumulation of putrescine. The relevance of these TPA-induced changes to the mechanism of tumor promotion was investigated using alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. DFMO applied to mouse skin (0.3 mg in 0.2 ml of solvent) or administered in the drinking water (1%) in conjunction with skin tumor promotion by TPA inhibited the formation of mouse skin papillomas by 50 and 90%, respectively. TPA-induced ODC activity and the accumulation of putrescine were almost completely inhibited. DFMO given in the drinking water decreased spermidine levels, but DFMO treatment by any route did not alter the spermine levels of mouse epidermis. DFMO decreased TPA-induced hyperplasia by 25 to 40%, and the TPA-caused increases in DNA synthesis and mitotic index were inhibited by 60 and 50%, respectively. Therefore, in mouse epidermis, enhanced cell proliferation can be dissociated from ODC induction and the accumulation of putrescine. At the tested dose levels and routes of administration, DFMO did not inhibit the inflammatory response to TPA in several tissues. These results provide evidence for an essential role of ODC induction and the accumulation of putrescine in tumor promotion by TPA and add strength to the proposal that DFMO may be a promising drug for the prevention and treatment of cancer in human beings.

UI	MeSH Term	Description	Entries
D007274	Injections, Intraperitoneal	Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall.	Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D009952	Ornithine	An amino acid produced in the urea cycle by the splitting off of urea from arginine.	2,5-Diaminopentanoic Acid,Ornithine Dihydrochloride, (L)-Isomer,Ornithine Hydrochloride, (D)-Isomer,Ornithine Hydrochloride, (DL)-Isomer,Ornithine Hydrochloride, (L)-Isomer,Ornithine Monoacetate, (L)-Isomer,Ornithine Monohydrobromide, (L)-Isomer,Ornithine Monohydrochloride, (D)-Isomer,Ornithine Monohydrochloride, (DL)-Isomer,Ornithine Phosphate (1:1), (L)-Isomer,Ornithine Sulfate (1:1), (L)-Isomer,Ornithine, (D)-Isomer,Ornithine, (DL)-Isomer,Ornithine, (L)-Isomer,2,5 Diaminopentanoic Acid
D009955	Ornithine Decarboxylase	A pyridoxal-phosphate protein, believed to be the rate-limiting compound in the biosynthesis of polyamines. It catalyzes the decarboxylation of ornithine to form putrescine, which is then linked to a propylamine moiety of decarboxylated S-adenosylmethionine to form spermidine.	Ornithine Carboxy-lyase,Carboxy-lyase, Ornithine,Decarboxylase, Ornithine,Ornithine Carboxy lyase
D011073	Polyamines	Amine compounds that consist of carbon chains or rings containing two or more primary amino groups.	Polyamine
D002455	Cell Division	The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.	M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D004817	Epidermis	The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of EPITHELIUM: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis).
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
D000518	Eflornithine	An inhibitor of ORNITHINE DECARBOXYLASE, the rate limiting enzyme of the polyamine biosynthetic pathway.	Difluoromethylornithine,alpha-Difluoromethylornithine,DL-alpha-Difluoromethylornithine,Eflornithine Hydrochloride,Eflornithine Monohydrochloride, Monohydrate,MDL-71,782 A,Ornidyl,RMI 71782,Vaniqa,alpha-Difluoromethyl Ornithine,DL alpha Difluoromethylornithine,MDL 71,782 A,MDL71,782 A,Ornithine, alpha-Difluoromethyl,alpha Difluoromethyl Ornithine,alpha Difluoromethylornithine