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Nicotinamide and Nicotinamide Analogues as Antitumor Promoters in Mouse Skin¹

Institut für Physiologische Chemie [A. L., G. S., K. M., H. H.] and Institut für Pathologie [M. D.] der Universität Hamburg, Martinistr. 52, 2000 Hamburg 20, Federal Republic of Germany

Phorbol ester-induced promotion of initiated NMRI mouse skin keratinocytes to papillomas could be largely prevented when nicotinamidelike inhibitors of poly(ADP-ribose)polymerase (nicotinamide, benzamide, 3-aminobenzamide) were applied simultaneously with 12-O-tetradecanoylphorbol-13-acetate (TPA). A similar suppression of tumor promotion by nicotinamide analogues was demonstrated in clone 41 JB6 epidermal cells which are promotable by TPA to anchorage-independent growth. The antipromotion effect of nicotinamide analogues, however, does not appear to come about by an inhibition of poly(ADP-ribose)polymerase. Acid analogues of nicotinamide, such as benzoic acid or 3-aminobenzoic acid which do not inhibit the polymerase, showed antipromotion activity similar to that of their corresponding amides. It could also be ruled out that these antipromoters mediate their effect on keratinocytes by a cytostatic action, by scavenging the promoter TPA in a chemical reaction, or by inhibiting protein kinase C. In initiated mouse skin, nicotinamide analogues strongly suppressed TPA-induced accumulation of inflammatory cells and vascular permeability, while epidermal hyperplasia was not significantly affected.

¹ This research was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 232).

² To whom requests for reprints should be addressed.

Received 1/ 5/89. Revised 11/20/89.