Inhibition of 12-O-tetradecanoylphorbol-13-acetate induction of ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse skin by ascorbic acid and ascorbyl palmitate.
The effects of topically applied 12-O-tetradecanoylphorbol-13-acetate (TPA) on the level of ascorbic acid in the epidermis and the effects of topically applied ascorbic acid, ascorbyl palmitate (a synthetic lipophilic derivative of ascorbic acid), palmitic acid and sorbitan monopalmitate on TPA-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 5 or 16 nmol of TPA resulted in a 45-50% decrease in the amount of ascorbic acid per mg protein in mouse epidermis at 5 h after TPA application. Large topical doses of ascorbic acid inhibited TPA-induced tumor promotion in mouse epidermis, but smaller doses were inactive. The topical application of relatively small doses of ascorbyl palmitate had a marked inhibitory effect on TPA-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse epidermis. Ascorbic acid, palmitic acid, and sorbitan monopalmitate were less effective than ascorbyl palmitate as inhibitors of tumor promotion. The topical application of 4 mumol of ascorbyl palmitate inhibited by 60-76% the induction of epidermal ornithine decarboxylase activity and DNA synthesis that occurred after a single topical application of 2 nmol of TPA whereas similar doses of ascorbic acid had no inhibitory effect. The topical application of 4 mumol of ascorbyl palmitate together with 5 nmol of TPA twice weekly for 20 weeks to previously initiated mice inhibited by 91% the number of tumors per mouse.
Smart
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RC
Laboratory of Experimental Carcinogenesis and Metabolism, Roche Institute of Molecular Biology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Huang
M T
MT
Han
Z T
ZT
Kaplan
M C
MC
Focella
A
A
Conney
A H
AH
D000287:Administration, Topical; D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004075:Diglycerides; D010169:Palmitic Acids; C044297:1,2-didecanoylglycerol; D019308:Palmitic Acid; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid