The objective of the present investigation was to compare the effects of three
ornithine decarboxylase inhibitors on tumoricidal macrophage and antitumor activities in vivo.
alpha-Difluoromethylornithine (DFMO), (2R,5R)-6-heptyne-2,5-diamine, and
alpha-(fluoromethyl)dehydroornithine methyl
ester (delta 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 delta 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. delta MFMOme was substantially more effective both as an
antitumor agent and in reducing
polyamines. Both DFMO and delta MFMOme augmented macrophage tumoricidal activity directed against B16F1 target cells. MAP had no effect on macrophage tumoricidal activity.
Lipopolysaccharide-stimulated macrophages from delta MFMOme-treated mice also exhibited an increase in
interleukin and
tumor necrosis factor levels. Furthermore, treatment with a known macrophage activator,
gamma-interferon, enhanced the antitumor activity of delta MFMOme. delta 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.