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Ability of the Ca²⁺ Ionophores A23187 and Ionomycin to Mimic Some of the Effects of the Tumor Promoter 12-O-Tetradecanoylphorbol-13-acetate on Hydroperoxide Production, Ornithine Decarboxylase Activity, and DNA Synthesis in Mouse Epidermis in Vivo¹

Anti-Cancer Drug Laboratory, Division of Biology, Kansas State University, Ackert Hall, Manhattan, Kansas 66506

When applied topically to the skin twice at a 48-h interval or thrice at 24-h intervals, 17 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) and 0.2 µmol of A23187 or ionomycin induce the same 3-fold increases of hydroperoxide (HPx) production in mouse epidermis. In contrast, these doses of Ca²⁺ ionophores applied once or twice at a 48-h interval produce only 3–8% of the 16- or 34-fold inductions of epidermal ornithine decarboxylase (ODC) activities caused by similar TPA treatments. However, these various Ca²⁺ ionophore treatments mimic entirely the stimulatory effects of TPA on epidermal DNA synthesis at 16 h and produce from 30 to 70% of the DNA responses to TPA at 32 h. Interestingly, the Ca²⁺ ionophore and TPA treatments applied thrice at 24-h intervals still produce above maximal or submaximal DNA responses, in spite of their very weak ODC-inducing activities or refractoriness against ODC induction. Treatment with -difluoromethylornithine plus methylglyoxal bis-(guanylhydrazone) (1.25 µmol each), which inhibits the activity of the polyamine-synthesizing enzymes, does not block the HPx and DNA responses to TPA. Conversely, 1.6–25-nmol doses of fluocinolone acetonide inhibit both TPA-induced HPx production and DNA synthesis, without affecting ODC induction. The results suggest that the magnitudes of Ca²⁺ ionophore- and TPA-induced DNA synthesis may be linked to HPx production rather than ODC induction. Each of these three responses appears to be essential but not sufficient for tumor promotion. A23187 may be a poor or incomplete skin tumor promoter because it lacks sufficient ODC-inducing activity and cannot fully maintain the prolonged stimulation of DNA synthesis required for hyperproliferation.

¹ This investigation was supported in part by the American Cancer Society (Grant BC-600), the University of Kansas Cancer Center (American Cancer Society Grant IN-115K), the Wesley Foundation of Wichita (Wesley Scholar Program: Molecular Biology and Cell Growth Regulation), BioServe Space Technologies, and the Center for Basic Cancer Research, Kansas State University. A preliminary report of this work was presented at the Eighty-First Annual Meeting of the American Association for Cancer Research, May 1990, Washington, DC (1).

² To whom requests for reprints should be addressed at Anti-Cancer Drug Laboratory, Division of Biology, Kansas State University, Ackert Hall, Manhattan, Kansas 66506.

Received 1/29/90. Accepted 6/15/90.