The anti-proliferative effects of 1,1'-[(methylethanediylidene)dinitrilo]
diguanidine [
methylglyoxal bis(guanylhydrazone)] and 1,1'-[(metHYLETHANEDIYLIDENE)dinitrilo]bis-(3-
aminoguaNIDINE) HAVE BEEN STUDIED IN Ehrlich
ascites carcinoma cells grown in
suspension cultures. Both compounds are potent inhibitors of
S-adenosyl-L-methionine decarboxylase from the tumour cells. In the presence of
putrescine (but not in its absence), the inhibition produced by 1,1'-[methylethanediylidene)dinitrilo]bis-(3-aminoguanadine) was apparently irreversible, as judged by persistent depression of the
enzyme activity even after extensive dialysis. The two compounds produced similar increases in
adenosylmethionine decarboxylase activity, which resulted from a striking stabilization of the
enzyme in cells grown in the presence of the drugs. The inhibitory effect of the two
diguanidine derivatives on the synthesis of
DNA and
protein became evident after an exposure of 4--8 h. At that time, the only change seen in tumour
polyamines in cells grown in the presence of the inhibitors was an increase in cellular
putrescine. To find out whether the compounds initially interfered with the energy production of the tumour cells, the cultures were grown in the presence of uniformly labelled
glucose, and the formation of
lactate, as well as the oxidation of the
sugar into CO2, were measured. The activation of glycolysis upon dilution of the tumour cells with fresh medium and the subsequent formation of labelled CO2 were siliar in control cells and in cells exposed to
methylglyoxal bis(buanylhydrazone), 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-
aminoguanidine) or diaminopropanol. Only a marginal decrease in the cellular content of
ATP was found in cells exposed to the inhibitors for 24 h. The
diguanidine-induced growth inhibition was fully reversed by low concentrations of exogenous
polyamines. However, the possibility remained that the reversal by
polyamines was due to a decrease of intracellular
diguanidine concentration. Our results indicate that the mode of action of 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-
aminoguanidine) is fully comparable to that of
methylglyoxal bis(guanylhydrazone), as regards stabilization of
adenosylmethionine decarboxylase and the appearance of growth inhibition in Ehrlich
ascites cells. The data tend to support the view that both compounds apparently have an early anti-proliferative effect unrelated to
polyamine metabolism.