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Differential Effects of Polyamine Homologues on the Prevention of DL--Difluoromethylornithine-mediated Inhibition of Malignant Cell Growth and Normal Immune Response¹

Divisions of Nephrology [A. B. S., M. S., R. A. M.] and Rheumatology [T. J. T.], Department of Medicine, Department of Environmental and Community Medicine [T. T.], and the Program in Clinical Pharmacology, Clinical Research Center [T. J. T.], University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903

Natural polyamines (putrescine, spermidine, and spermine) are ubiquitous cellular cations that play an important role in cell proliferation and differentiation. Ornithine decarboxylase is the first and a rate-limiting enzyme in the biosynthesis of polyamines. Polyamine depletion using DL--difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, has been shown to suppress cell growth in a variety of settings, including those of tumor and lymphocyte proliferation. The objective of the present investigation was to examine the inhibitory effects of DFMO on a variety of murine in vitro immune respenses, including lymphocyte proliferation in response to T-cell mitogen (concanavalin A), B-cell mitogen (lipopolysaccharide), and alloantigen as well as cytotoxicity. DFMO-mediated inhibition of cell proliferation in these cases correlated with depletion of intracellular polyamines. The inhibitory effects of DFMO were reversed by polyamine repletion with putrescine. Putrescine also reversed the growth-inhibitory effects of DFMO on 4 tumor cell lines that we tested: 28-13-3S, YAC-1, P-815, and K562. However, putrescine homologues exhibited a differential effect in preventing DFMO-mediated inhibition of cell growth in normal lymphocytes and cancer cell lines. Only putrescine homologues containing a shorter methylene chain were effective in preventing the growth-inhibitory action of DFMO on normal immune response. In contrast, only the longer chain homologue 1,5-diaminopentane overcame the effect of DFMO on tumor cell growth. These findings suggest that supplementation with selected polyamine homologues may sustain normal immune response in DFMO-treated individuals while effectively suppressing malignant cell growth. The potential clinical relevance of these observations is discussed.

¹ This work was supported, in part, by the National Institutes of Health grants DK 40504 (R. A. M.), AR 39020 (T. J. T.), and CA 42439 (T. T.).

² To whom requests for reprints should be addressed.

Received 11/ 7/90. Accepted 1/24/92.