Effect of N¹,N¹⁴‐bis‐(ethyl)‐homospermine (BE‐4–4‐4) on the growth of U‐251 MG and SF‐188 human brain tumor cells

We studied the effects of the spermine analogue N,N¹⁴‐bis‐(ethyl)‐homospermine (BE‐4–4‐4) on growth, survival and polyamine levels in cultured U‐251 MG and SF‐188 human brain tumor cells. After 48 hr of treatment at concentrations of 1 μM or higher, BE‐4–4‐4 accumulated in cells with a concomitant decrease in intracellular putrescine, spermldine and spermine concentrations. Growth inhibition by 10 μM BE‐4–4‐4 began at 6 hr and peaked between 16 and 24 hr. The analogue was also increasingly cytotoxic with doses between 1 and 10 μM and with treatment times between 16 and 48 hr. Polyamines added 1 day after BE‐4–4‐4 lowered the intracellular concentrations of the analogue but did not reverse its growth‐inhibitory activity. When added simultaneously with the analogue, however, polyamines caused a decrease in analogue concentration that was accompanied by a block to the growth Inhibition. BE‐4–4‐4 has a higher affinity for DNA than spermine has, but is less able to aggregate DNA. Its growth‐inhibitory and cytotoxic effects support our hypothesis that polyamine analogues that enter cells and replace natural polyamines at DNA binding sites, without fulfilling their biologic functions, should act as antiproliferative agents.