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

Journal Article · Fri Oct 01 00:00:00 EDT 1982 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.79.19.6028· OSTI ID:5335601

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

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 ..cap alpha..-difluoromethylornithine (CHF/sub 2/-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 ..mu..g) treatment was approx. = 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 greately enhanced papilloma yield. CHF/sub 2/-Orn, given orally or intraperitoneally, abolished the TPA-induced OrnDCase activity and Put accumulation in mouse epidermis. The reduction of polyamine accumulation by CHF/sub 2/-Orn was directly proportional to reduction of tumor size. CHF/sub 2/-Orn administered in a two-stage (TPA-mezerein) promotion protocol reduced tumor size, inhibited by 65 to 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. CHF/sub 2/-Orn provided considerably less effect on tumorigenesis when administered with the TPA portion of the protocol, and CHF/sub 2/-Orn did not inhibit the induction of dark basal keratinocytes by TPA. Based on our results with CHF/sub 2/-Orn, we suggest that regulation of polyamine biosynthesis, particularly Put, is a critical factor in stage II promotion.

• Research Organization: Oak Ridge National Lab., TN
• DOE Contract Number: W-7405-ENG-26
• OSTI ID: 5335601
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 79; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

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59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMALS
AROMATICS
BIOLOGICAL EFFECTS
BIOSYNTHESIS
CARBON-CARBON LYASES
CARBOXY-LYASES
CARCINOGENS
CHEMICAL ANALYSIS
CONDENSED AROMATICS
CORRELATIONS
DATA
DECARBOXYLASES
DIMETHYLBENZANTHRACENE
DISEASES
ENZYME ACTIVITY
ENZYMES
ESTERS
EXPERIMENTAL DATA
INFORMATION
LYASES
MAMMALS
MICE
NEOPLASMS
NUMERICAL DATA
ONTOGENESIS
ORGANIC COMPOUNDS
PHORBOL ESTERS
PROMOTERS
PUTRESCINE
QUANTITATIVE CHEMICAL ANALYSIS
RODENTS
SPERMINE
SYNTHESIS
VERTEBRATES