The
spermine analog N1,N11-diethylnorspermine (DE-333, also known as
DENSPM or
BENSPM) is regarded as the most potent known inducer of the
polyamine catabolic
enzyme,
spermidine/
spermine N1-acetyltransferase (SSAT), increasing activity by more than 200- to 1000-fold in certain cell types. The relative ability of a series of eight systematically modified
DE-333 analogs to affect SSAT expression was examined in Malme-3M human
melanoma cells, one of several cell lines known to be especially responsive to induction of this
enzyme. In particular, we examined the relative contribution of induction of
enzyme mRNA and prolongation of
enzyme half-life to analog-mediated increases in
enzyme activity. Induction of
enzyme mRNA was most influenced by intra-
amine carbon distances; relative effectiveness was found to be proportional to the number of three-
carbon units. Stabilization of
enzyme was most determined by the terminal N-alkyl substituent size; among methyl, ethyl and propyl groups, methyl was least effective. Thus,
DE-333, which most potently induces SSAT
mRNA and effectively stabilizes SSAT
enzyme activity, produces the greatest increase in
enzyme activity. Although other contributing mechanisms may be involved, the relative abilities of the various analogs to induce
enzyme activity is at least partially attributable to their combined effects on
enzyme mRNA and
protein half-life. These data reveal the highly sensitive structure-activity relationships that underlie and control
spermine analog induction of SSAT activity. Pending further definition of the relationship between SSAT induction and antitumor growth and toxicity in vivo, these relationships may be used to optimize therapeutic efficacy.