INHIBITION OF T-CELL MITOGENESIS BY NITROFURANS

A group of nitrofurans (5-nitro-2-furaldehyde, nifuroxime, nitrofurazone, nitrofurantoin, 5-nitro-2-furoic acid and 2-nitrofuran) were evaluated for inhibition of mitogenesis (DNA synthesis) in human peripheral blood T cells. T cells, either triggered by phorbol myristate acetate (PMA) or in the presence of accessory cells, were activated with a specific mitogen [phytohemagglutin (PHA), concanavalin A (ConA), or anti-CD3] and the amount of tritiated thymidine incorporated into DNA was determined. The results obtained indicate that nitrofurans inhibit mitogenesis irrespective of activator. 5-Nitro-2-furaldehyde was much more inhibitory than the other compounds, while 2-nitrofuran was less inhibitory. When the aldehyde group (5-nitro-2-furaldehyde) was replaced by a carboxyl group (5-nitro-2-furoic acid), the inhibitory activity was also reduced greatly. These results show that while the nitro group alone confers inhibitory activity to the furan ring, the group at the 2 position is crucial. In general, the mitogenic response of purified T cells (lacking accessory cells) triggered by PMA (phorbol ester) was inhibited less than that of the T cell-accessory cell system. With the latter, 50% inhibition of T cell mitogenesis was achieved by nifuroxime, nitrofurazone, and nitrofurantoin at 45-51 and 34-39-mu-M with PHA and ConA respectively. When purified T cells were used, the values were 71-85 and 55-60-mu-M respectively. For a given drug concentration, mitogenesis was more inhibited when induced by ConA or anti-CD3 than by PHA. The importance of using a single cell system (purified T cells) was emphasized by the interesting finding that only this system showed enhancement of mitogenesis, up to 35-40% at low drug levels. With the exception of the nitrofuraldehyde, the nitrofurans at strongly inhibitory levels were only moderately cytotoxic, exhibiting 62-85% cell survival after exposure to drug for 68 hr. Our results suggest that nitrofurans inhibit T cell mitogenesis by a relatively non-toxic mechanism; these results are comparable to those obtained for mammalian cells under aerobic conditions.