INHIBITION OF LUNG TUMORIGENESIS BY NSAIDS - A WORKING HYPOTHESIS

A 7-week treatment with the tobacco carcinogen NNK induced 8-10 lung a denomas per A/J mouse. NNK suppressed humoral and cellular immune resp onses and increased plasma PGE(2) and LTB4 levels. This protocol is pa rticularly suitable for testing NSAIDs and lipoxygenase inhibitors as cancer preventive agents. Sulindac and ASA inhibited lung tumorigenese s by 52 and 60%, respectively, attenuated the suppressive effect of NN K, and lowered the plasma PGE(2) to basal levels. In contrast, naproxe n neither inhibited lung tumorigenesis nor increased NNK-suppressed NK cell cytoxicity. NSAIDs and lipoxygenase inhibitors had additive prev entive efficacies against NNK-induced lung tumorigenesis. However, sul indac was not effective in preventing lung tumorigenesis induced by B[ a]P, which lacks immunosuppressive activity. These results and those p ublished by other investigators lead to the following hypothesis: Reac tive intermediates derived from NNK interfere with the stimulation of the complex NF-kappa B/I kappa B. NF-kappa B is involved in the regula tion of immune and inflammatory responses. The authors propose that NN K-derived intermediates induce the expression of COX-2 and lipoxygenas e involved in NNK activation. This hypothesis provides a rationale for the lack of efficacy of naproxen to prevent tumorigenesis, to attenua te NNK-induced synthesis of PGE(2), and to increase NNK cell cytotoxic ity. According to this hypothesis, PGE(2) synthesis and induction of a poptosis contribute to varying degrees to the mechanism of cancer prev ention.