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Comparison of the effect of sn-1,2-didecanoylglycerol and 12-O-tetradecanoylphorbol-13-acetate on cutaneous morphology, inflammation and tumor promotion in CD-1 mice
Toxicology Program, North Carolina State University Raleigh, NC 27695-7633
1Department of Chemical Biology and Pharmacognosy, College of Pharmacy Rutgers, The State University of New Jersey Piscataway, NJ 08855-0789
2Roche Research Center Hoffmann-La Roche Inc., Nutley, NJ 07110, USA
Since sn-1,2-didecanoylglycerol mimics 12-O-tetradecanoylphorbol-13-acetate (FPA) by inducing ornithine decarboxylase activity and stimulating DNA synthesis in mouse epidermis [Smart,R.C., Huang,M.-T. and Conney,A.H. Carcinogenesis, 7, 1865(1986)], we have investigated morphological changes induced by TPA and sn-1,2-didecanoylglycerol in the epidermis and we have also examined sn-1,2-didecanoylglycerol as a possible complete tumor promoter. It wasdetermined that topical application of 2.5 or 10 µmol of sn-1,2-didecanoylglycerol induced epidermal ornithine decarboxylase activity to about the same extent as the application of 1 or 2 nmol of TPA respectively. Therefore, these doses of TPA and sn-1,2-didecanoylglycerol were used in most of our studies. Single or multiple application (2 x /week for 4 weeks) of 1, 2 or 5 nmol of TPA to the skin of CD-1 mice produced a dose-dependent increase in the number of epidermal non-cornified cell layers, epidermal thickness, leukocyte infiltration and intracellular edema. In contrast, neither single nor multiple application (2 x /week for 4 weeks) of 2.5 or 10 µmol sn-1,2-didecanoylglycerol produced any of these responses. However, when 5 µmol sn-1,2-didecanoyl- glycerol was applied topically twice a day (10 µmol/day) for 5 days there was a significant increase in the number of epidermal non-cornified cell layers and epidermal thickness. The effects of TPA and sn-1,2-didecanoylglycerol were compared using the mouse ear inflammation model. Application of TPA caused edema, but sn-1,2-didecanoylglycerol had little or no effect. sn-1,2-Didecanoylglycerol was then evaluated as a complete tumor promoter utilizing the mouse skin two-stage model. CD-1 mice were initiated with 200 nmol 7,12-dimethythenz[a]anthracene and then treated wIth 1 nmol TPA or 2.5 µmol sn-1,2-didecanoylglycerol twice a week for 28 weeks. A28 weeks, 28% of the mice treated with TPA had developed tumors, while none of the mice treated with 2.5 µmol sn-1,2-didecanoylglycerol developed tumors. The data indicate that topical application of 2.5 µmol sn-1,2-didecanoylglycerol induced ornithine decarboxylase activity to the same extent as a tumor-promoting dose of 1 nmol TPA, but it did not cause morphologial changes in the epidermis when applied once or when applied twice a week for 4 weeks and did not function as a complete tumor promoter when applied twice a week for 28 weeks. Since more frequent applications of sn-1,2-didecanoylglycerol (5 µmol twice a day
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