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Events Associated with Mouse Skin Tumor Promotion with Respect to Arachidonic Acid Metabolism: A Comparison between SENCAR and NMRI Mice¹

The University of Texas System Cancer Center, Science Park—Research Division, Smithville, Texas 78957 [S. M. F., T. J. S.], and German Cancer Research Institute, Institute of Biochemistry, Heidelberg, Federal Republic of Germany [G. F., F. M.]

NMRI and SENCAR, two stocks of mice commonly used in multistage skin carcinogenesis studies, were compared with respect to the effects of inhibitors of arachidonic acid metabolism for the following 12-O-tetradecanoylphorbol-13-acetate (TPA)-elicited events: tumor promotion, DNA synthesis in vivo and in vitro, ornithine decarboxylase induction, and prostaglandin (PG) E₂ synthesis. Previous work had shown that the cyclooxygenase inhibitor indomethacin enhanced TPA promotion in SENCAR mice. We report here that over the same dose range (50 to 200 µg) indomethacin caused a dose-dependent inhibition of promotion in NMRI mice. Significant reversal of this inhibition was achieved with concomitant application of 10 µg PGF₂ but not PGE₂. DNA synthesis studies showed that low doses of indomethacin and flurbiprofen increased TPA-stimulated DNA synthesis in primary cultures from SENCAR mice; indomethacin suppressed this response in NMRI cultures. In vivo DNA synthesis studies showed the same pattern: indomethacin enhanced TPA-stimulated DNA synthesis in SENCAR mice but inhibited in NMRI mice. Other classes of inhibitors of arachidonate metabolism (i.e., the cyclooxygenase-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and phenidone and the phospholipase A₂ inhibitor dibromoacetophenone) had inhibitory activity in vitro and in vivo in both stocks of mice. Indomethacin was found to inhibit TPA-induced ornithine decarboxylase activity to the same extent in both mice. Indomethacin was also very effective in inhibiting TPA-induced PGE₂ synthesis in both stocks of mice. 5,8,11,14-Eicosatetraynoic acid and phenidone were likewise suppressive in both stocks of mice. It is concluded that the NMRI and SENCAR mice respond similarly to TPA with respect to promotion, DNA synthesis, ornithine decarboxylase induction, and PG synthesis. The difference appears to be in the degree of involvement of the lipoxygenase pathway.

¹ This study was supported by USPHS grants CA-34443 (S. M. F.), CA-34521, CA-34962, and CA-34890 (T. J. S.), and by the Deutsche Forschungsgemeinschaft (G. F., F. M.).

² To whom requests for reprints should be addressed.

Received 12/ 1/86. Revised 3/ 4/87. Accepted 3/20/87.

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