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Effects of Three Irreversible Inhibitors of Ornithine Decarboxylase on Macrophage-mediated Tumoricidal Activity and Antitumor Activity in B16F1 Tumor-bearing Mice

Merrell Dow Research Institute, Cincinnati, Ohio 45215

The objective of the present investigation was to compare the effects of three ornithine decarboxylase inhibitors on tumoricidal macrophage and antitumor activities in vivo. -Difluoromethylornithine (DFMO), (2R,5R)-6-heptyne-2,5-diamine, and -(fluoromethyl)dehydroornithine methyl ester (MFMOme) were administered continuously in drinking water starting on Day 1 to B16F1 tumor-bearing mice. DFMO, (2R,5R)-6-heptyne-2,5-diamine, and MFMOme reduced B16F1 tumor growth, measured on Day 18, up to 87, 79, and 95%, respectively. Similarly, all three ornithine decarboxylase inhibitors reduced B16F1 putrescine and spermidine levels. MFMOme was substantially more effective both as an antitumor agent and in reducing polyamines. Both DFMO and MFMOme augmented macrophage tumoricidal activity directed against B16F1 target cells. MAP had no effect on macrophage tumoricidal activity. Lipopolysaccharide-stimulated macrophages from MFMOme-treated mice also exhibited an increase in interleukin and tumor necrosis factor levels. Furthermore, treatment with a known macrophage activator, -interferon, enhanced the antitumor activity of MFMOme. MFMOme did not alter natural killer cell activity; however, cytolytic T-lymphocyte induction was reduced by 40 to 50%. These results demonstrate that, in addition to their established antitumor activity, ornithine decarboxylase inhibitors may also potentiate specific tumoricidal effector cell generation in vivo.

¹ To whom requests for reprints should be addressed.

Received 2/ 1/90. Revised 4/12/90.