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alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. 1982

C E Weeks, and A L Herrmann, and F R Nelson, and T J Slaga

The role of ornithine decarboxylase (OrnDCase, EC 4.1.1.17) and of the polyamines [putrescine (Put), spermidine (Spd), and spermine (Spm)] in mouse skin tumor promotion was investigated by the use of alpha-difluoromethylornithine (CHF2-Orn), an enzyme-activated irreversible inhibitor of OrnDCase. 12-O-Tetradecanoylphorbol 13-acetate (TPA), mezerein, and ethyl phenylpropiolate (EPP) were employed as complete, stage II specific, and nonpromoting agents, respectively. TPA and mezerein, but not EPP, provided for a dose-dependent increase in tissue Put accumulation. The Put level in papillomas developed by TPA (2 micrograms) treatment was approximately equal to 15-fold higher than that of the surrounding skin tissue; Spd accumulation was 2- to 3-fold greater in the papillomas. Put administered (intraperitoneally) with TPA greatly enhanced papilloma yield. CHF2-Orn, given orally or intraperitoneally, abolished the TPA-induced OrnDCase activity and Put accumulation in mouse epidermis. The reduction of polyamine accumulation by CHF2-Orn was directly proportional to reduction of tumor size. CHF2-Orn administered in a two-stage (TPA-mezerein) promotion protocol [Slaga, T. J., Fischer, S. M., Nelson, K. G. & Gleason, G. L. (1980) Proc. Natl. Acad. Sci. USA 77, 3659-3663; Slaga, T. J., Klein-Szanto, A. J. P., Fischer, S. M., Weeks, C. E., Nelson, K. & Major, S. (1980) Proc. Natl. Acad. Sci. USA 77, 2251-2254] reduced tumor size, inhibited by 65-70% the number of papillomas per mouse, and decreased by 40% the percentage of mice with tumors when given with the stage II agent mezerein. CHF2-Orn provided considerably less effect on tumorigenesis when administered with the TPA portion of the protocol, and CHF2-Orn did not inhibit the induction of dark basal keratinocytes by TPA. Based on our results with CHF2-Orn, we suggest that regulation of polyamine biosynthesis, particularly Put, is a critical factor in stage II promotion.

UI MeSH Term Description Entries
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
D009374 Neoplasms, Experimental Experimentally induced new abnormal growth of TISSUES in animals to provide models for studying human neoplasms. Experimental Neoplasms,Experimental Neoplasm,Neoplasm, Experimental
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
D010703 Phorbol Esters Tumor-promoting compounds obtained from CROTON OIL (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. Phorbol Diester,Phorbol Ester,Phorbol Diesters,Diester, Phorbol,Diesters, Phorbol,Ester, Phorbol,Esters, Phorbol
D011073 Polyamines Amine compounds that consist of carbon chains or rings containing two or more primary amino groups. Polyamine
D002262 Carboxy-Lyases Enzymes that catalyze the addition of a carboxyl group to a compound (carboxylases) or the removal of a carboxyl group from a compound (decarboxylases). EC 4.1.1. Carboxy-Lyase,Decarboxylase,Decarboxylases,Carboxy Lyase,Carboxy Lyases
D002273 Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D004224 Diterpenes Twenty-carbon compounds derived from MEVALONIC ACID or deoxyxylulose phosphate. Diterpene,Diterpenes, Cembrane,Diterpenes, Labdane,Diterpenoid,Labdane Diterpene,Norditerpene,Norditerpenes,Norditerpenoid,Cembranes,Diterpenoids,Labdanes,Norditerpenoids,Cembrane Diterpenes,Diterpene, Labdane,Labdane Diterpenes
D005260 Female Females
D000480 Alkynes Hydrocarbons with at least one triple bond in the linear portion, of the general formula Cn-H2n-2. Acetylenic Compounds,Alkyne,Acetylenes

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