Compared to 12-O-tetradecanoylphorbol-13-acetate (TPA), the phorbol ester 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate (4-O-methyl-TPA) is only a weak skin irritant and tumor promoter. When topically applied to mouse skin, 400 nmol 4-O-methyl-TPA induce hyperproliferation of epidermis in vivo to approximately the same extent as do 10 nmol TPA. However, in contrast to TPA, 4-O-methyl-TPA-induced proliferation is not followed by sustained epidermal hyperplasia. In addition, the methyl ether of TPA does not cause early prostaglandin accumulation, and its hyperproliferative effect is insensitive to indomethacin inhibition.

Contrary to the action of TPA, 4-O-methyl-TPA induces neither an early increase in the rate of phospholipid turnover nor an early increase in ornithine decarboxylase activity or polyamine accumulation in epidermis and does not desensitize epidermis to the effects of β-adrenergic agonists and epidermal G1 chalone. Finally, 4-O-methyl-TPA is only a weak atimulator of epidermal cyclic adenosine 3′:5′-monophosphate phosphodiesterase activity. Consequently, it is concluded that the mechanism of action of 4-O-methyl-TPA as a skin mitogen is different from that of TPA. Whereas TPA evokes prostaglandin-dependent and chalone-insensitive hyperplastic development of epidermis (hyperplastic transformation), i.e., probably a relapse to the neonatal state, 4-O-methyl-TPA apparently stimulates nothing but normal everyday tissue regeneration. In this respect, treatment with 4-O-methyl-TPA resembles a nondamaging stimulus of epidermal cell proliferation (observed, for example, with skin massage), whereas TPA evokes a response which is characteristic for epidermal injury.

Considering these fundamental differences in biological action between TPA and its methyl ether, 4-O-methyl-TPA is concluded to be an unsuitable negative control compound for studies on the biological effects of phorbol ester tumor promoters.

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This work was partially supported by grants from the Deutsche Forschungs-gemeinschaft and the Wilheim- and Maria-Meyenburg-Foundation.

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