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Effect of Dietary Arginine Restriction upon Ornithine and Polyamine Metabolism during Two-Stage Epidermal Carcinogenesis in the Mouse

Division of Biomedical Sciences and Department of Biochemistry, University of California, Riverside, California 92521

Polyamine synthesis is required in normal or neoplastic tissues if they are to continue to grow or divide. The highly inducible enzyme ornithine decarboxylase (ODC) catalyzes the conversion of ornithine to putrescine as the initial step in polyamine biosynthesis. The level of substrate pools of ornithine in cultured cells has been reported to markedly alter mitogen-induced ODC activity, putrescine accumulation, and DNA synthesis (V. Wu and C. V. Byus, Biochim. Biophys. Acta, 804: 89–99, 1984; V. Wu et al., Cancer Res., 41: 3384–3391, 1981). We attempted to limit the amount of ornithine available for polyamine biosynthesis in an animal by using a dietary approach. Since arginine serves as one of the immediate bisosynthetic precursors of ornithine, female CD-1 mice were placed on a special synthetic amino acid diet deficient in arginine. The ability of this arginine-free diet to alter epidermal ornithine and polyamine metabolism and tumorigenesis was assessed in the mouse two-stage model of skin carcinogenesis.

The basal level of ornithine in the epidermis in control animals receiving the amino acid complete diet was very high compared to other tissues (155 nmol/mg protein). However, when the mice were fed the isocaloric arginine-free diet for a 2-week period, the levels of epidermal ornithine and arginine decreased by 40% (P < 0.01). This reduction was blocked by the addition of 2% ornithine to the drinking water of the arginine-restricted animals. Acute administration of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) to the epidermis caused a transient (4 and 8 h) reduction in ornithine and arginine but not lysine in the animals receiving the control, and ornithine-supplemented diets.

The animals fed the special arginine-free diet exhibited a 40–50% reduction in tumor multiplicity or papillomas/mouse (P < 0.05) and had a significantly lower tumor incidence or percentage of animals with tumors throughout a 19-week promotion period (P < 0.02). However, the major effect of arginine restriction was consistent with an increase in tumor latency. The addition of ornithine completely reversed the reduction in the rate and extent of tumorigenesis in the arginine-free animals.

The accumulation of putrescine (but not spermidine or spermine) in the epidermis following a single administration of TPA was significantly reduced in the animals receiving the arginine-free diet. The papillomas or tumors from the animals deprived of arginine had markedly reduced (<35%) levels of putrescine compared to the tumors from control animals, and appeared to be more sensitive to dietary arginine restriction than was the chronically promoted but untransformed epidermis. The large increase in epidermal ODC activity brought about by a single treatment with TPA was not altered reproducibly in the arginine-restricted animals. However, animals given ornithine supplementation to the arginine-free or amino-acid complete diet exhibited a consistent 75% reduction in ODC activity following TPA. Dietary arginine limitation had no measurable effect upon acute TPA-stimulated DNA or protein synthesis in the epidermis. The data support the hypothesis, but do not prove conclusively, that the diminished tumorigenesis observed in the animals restricted in dietary arginine was a result of lowered pools of ornithine and the subsequent inhibition of putrescine biosynthesis.

¹ To whom requests for reprints should be addressed. Supported by NIH Grant CA45707, California Cancer Research Coordinating Committee grant, and assistance from the Academic Senate Research Committee at University of California, Riverside, CA to C. V. B.

Received 11/20/90. Accepted 3/26/91.

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