The objective of this proposal is to examine the tumor promotion mechanism with special reference to the role of cyclic nucleotides and other agents in the promotion process. An understanding of the relationship between promotion inhibitors, such as protease inhibitors and hormones, and cyclic nucleotides may provide a basic understanding of cancer promotion and thus aid in the control of cancer, particularly that from environmental sources. We have shown that tumor promotion appears to involve a decrease in cyclic AMP, and that theophylline, which raises skin cyclic AMP, inhibits promotion. We will study the effects of the promoter TPA, on cyclic AMP and cyclic GMP levels in mouse skin and attempt to correlate these effects with metabolic and other alterations induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The effects of TPA and the role of cyclic nucleotides on protein phosphorylation will be determined. The role of calcium, often involved in cyclic nucleotide effects, will also be studied. TPA reacts with membrane gangliosides which is a likely primary event. The role of gangliosides in the inhibition of promotion will also be examined. These studies could aid in clarifying carcinogenic mechanisms and thus help in the management of human cancer.