INVESTIGATIONS OF THE MECHANISM BY WHICH MAMMALIAN-CELL GROWTH IS INHIBITED BY N1N12-BIS(ETHYL)SPERMINE

N1N-12-Bis(ethyl)spermine (BESM) and related compounds are powerful in hibitors of cell growth that may have potential as anti-neoplastic age nts [Bergeron, Neims, McManis, Hawthorne, Vinson, Bortell and Ingeno ( 1988) J. Med. Chem. 31,1183-1190]. The mechanism by which these compou nds bring abbut their effects was investigated by using variant cell l ines in which processes thought to be altered by these agents are pert urbed. Comparisons between the response of these cells and of their pa rental equivalents to BESM, N1N-11-bis(ethyl)norspermine, N1N-14-bis(e thyl)homospermine and N1N8-bis(ethyl)spermidine were then made. It was found that D-R cells, an L1210-derived line that over-expresses ornit hine decarboxylase, were not resistant to these compounds. This indica tes that the decrease in ornithine decarboxylase is not critical for t he action of the compounds on cell growth. Furthermore, although polya mine levels were decreased in the D-R cells, the content was not total ly depleted, indicating that such depletion is also not essential for the anti-proliferative effect. Two cell lines lacking mitochondrial DN A (human 143B206 cells and chicken DU3 cells) did not differ in sensit ivity to BESM from their parental 143BTK- and DU24 cells. Furthermore, the inhibition of respiration in L1210 cells in response to BESM deve loped more slowly than the inhibition of growth. Thus it appears that the inhibitions of mitochondrial DNA synthesis and of mitochondrial re spiration are also not primary factors in the anti-proliferative effec ts of these polyamine analogues. The inhibition of growth did, however , correlate with the intracellular accumulation of the analogues. It a ppears that the bis(ethyl)polyamine derivatives act by binding to intr acellular target molecules and preventing macromolecular synthesis. Th e decline in normal polyamines may facilitate such binding, but is not essential for growth arrest.