DIFFERENTIAL-EFFECTS OF POLYAMINE HOMOLOGS ON THE PREVENTION OF DL-ALPHA-DIFLUOROMETHYLORNITHINE-MEDIATED INHIBITION OF MALIGNANT-CELL GROWTH AND NORMAL IMMUNE-RESPONSE

Natural polyamines (putrescine, spermidine, and spermine) are ubiquito us cellular cations that play an important role in cell proliferation and differentiation. Ornithine decarboxylase is the first and a rate-l imiting enzyme in the biosynthesis of polyamines. Polyamine depletion using DL-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithi ne decarboxylase, has been shown to suppress cell growth in a variety of settings, including those of tumor and lymphocyte proliferation. Th e objective of the present investigation was to examine the inhibitory effects of DFMO on a variety of murine in vitro immune responses, inc luding lymphocyte proliferation in response to T-cell mitogen (concana valin A), B-cell mitogen (lipopolysaccharide), and alloantigen as well as cytotoxicity. DFMO-mediated inhibition of cell proliferation in th ese cases correlated with depletion of intracellular polyamines. The i nhibitory effects of DFMO were reversed by polyamine repletion with pu trescine. Putrescine also reversed the growth-inhibitory effects of DF MO on 4 tumor cell lines that we tested: 28-13-3S, YAC-1, P-815, and K 562. However, putrescine homologues exhibited a differential effect in preventing DFMO-mediated inhibition of cell growth in normal lymphocy tes and cancer cell lines. Only putrescine homologues containing a sho rter methylene chain were effective in preventing the growth-inhibitor y action of DFMO on normal immune response. In contrast, only the long er chain homologue 1,5-diaminopentane overcame the effect of DFMO on t umor cell growth. These findings suggest that supplementation with sel ected polyamine homologues may sustain normal immune response in DFMO- treated individuals while effectively suppressing malignant cell growt h. The potential clinical relevance of these observations is discussed .