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Synthetic Lipid Second Messenger sn-1,2-Didecanoylglycerol: A Complete Tumor Promoter in Mouse Skin¹

Department of Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633 [R. C. S., K. J. M., L. A. H.] and Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855-0789 [A. H. C.]

sn-1,2-Didecanoylglycerol, a synthetic lipid second messenger and model diacylglycerol, was evaluated as a complete skin tumor promoter in CD-1 mice. In addition, sn-1,2-dioctanoylglycerol, sn-1,2-didecanoylglycerol, the second stage tumor promoter mezerein, and the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for their ability to stimulate epidermal protein kinase C activity in vitro. All four compounds stimulated epidermal protein kinase C activity utilizing lysine-rich histone as the phosphate acceptor substrate. sn-1,2-Dioctanoylglycerol and sn-1,2-didecanoylglycerol stimulated epidermal protein kinase C activity to a maximum velocity similar to that obtained when the enzyme was stimulated with TPA; however, about 1000 times greater concentration of the sn-1,2-diacylglycerols was required. sn-1,2-Didecanoylglycerol was evaluated as a complete skin tumor promoter in CD-1 mice utilizing a dosing regimen demonstrated to produce epidermal hyperplasia. Mice were initiated with 200 nmol 7,12-dimethylbenz[a]anthracene. One week later the mice received twice daily topical applications of 1 nmol TPA, 2 µmol sn-1,2-didecanoylglycerol or 5 µmol sn-1,2-didecanoyglycerol, 5 days/week. Additional initiated mice received twice weekly topical applications of 2 or 5 nmol TPA. Initiated mice treated with 5 nmol TPA twice weekly or with 1 nmol TPA twice daily for 5 days/week (cumulative weekly doses of 10 nmol TPA) responded similarly, based on the tumor incidence and the average number of tumors per mouse. Initiated mice treated with 2 or 5 µmol sn-1,2-didecanoylglycerol twice daily developed tumors in a dose-dependent manner. Initiated mice treated with 5 µmol sn-1,2-didecanoylglycerol twice daily developed many tumors, and at 20 weeks there was a 74% tumor incidence and an average of 6.0 tumors/mouse. At 20 weeks, 24% of the initiated mice treated with 2 µmol sn-1,2-didecanoylglycerol twice daily developed tumors, with an average of 1.1 tumors/mouse. Mice which were not initiated but treated twice daily with 5 µmol sn-1,2-didecanoylglycerol for 20 weeks did not develop any tumors. These data demonstrate that the representative synthetic lipid second messenger sn-1,2-didecanoylglycerol, like TPA, is a complete tumor promoter in DMBA-initiated mouse skin.

¹ This research was supported in part by American Cancer Society Grant BC-644. This is Paper 12175 of the Journal Series of the NC Agricultural Research Service, Raleigh, NC 27695-7601.

² To whom requests for reprints should be addressed.

Received 3/ 1/89. Revised 5/ 4/89. Accepted 5/ 9/89.

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