The effects of the potent
spermine synthase inhibitor
S-adenosyl-1,12-diamino-3-thio-9-azadodecane (
AdoDatad) on
polyamine biosynthesis have been studied in transformed mouse fibroblasts (SV 3T3 cells) and in mouse
leukemia cells (L1210). A dose-dependent decrease in intracellular
spermine concentration was observed in both cell lines when grown in the presence of the inhibitor. A major difference in the effects seen in these two cell lines was the cytotoxicity observed in L1210 cells exposed to the inhibitor, which contrasted with little or no effects on growth of SV 3T3 cells treated similarly. Oxidative metabolism of the
drug in L1210 cells was suggested by the fact that addition of
aminoguanidine, an
amine oxidase inhibitor, to the cell cultures ablated the cytotoxic effects of the inhibitor. Complete analysis of intracellular
polyamines was carried out, together with analysis of
S-adenosylmethionine,
decarboxylated S-adenosylmethionine, and the inhibitor. These analyses revealed that, although the inhibitor had a dramatic effect on
spermine biosynthesis in the cells studied, a compensatory increase in
spermidine biosynthesis was observed. This resulted in no change in total
polyamine concentrations in cells treated with inhibitors of either
spermine synthase or
spermidine synthase (Pegg et al., 1982) alone or in combination. In all cases, the concentration of the aminopropyl donor
decarboxylated S-adenosylmethionine increased dramatically, thus allowing for the observed maintenance of total
polyamine levels even in the presence of either one or both potent inhibitors of the aminopropyltransferases. Oxidative metabolism of the inhibitor complicates the interpretation of experiments carried out in the absence of
amine oxidase inhibitors such as
aminoguanidine.(ABSTRACT TRUNCATED AT 250 WORDS)