Differential effects of polyamine homologues on the prevention of DL-alpha-difluoromethylornithine-mediated inhibition of malignant cell growth and normal immune response.
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-alpha-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 responses, 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.
Singh
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Division of Nephrology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903.
Thomas
T J
TJ
Thomas
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T
Singh
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M
Mann
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RA
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003208:Concanavalin A; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D000518:Eflornithine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007536:Isomerism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008223:Lymphoma; D008297:Male; D012515:Mast-Cell Sarcoma; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011073:Polyamines / Q000494:pharmacology*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D011073:Polyamines; D003208:Concanavalin A; D013096:Spermine; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine