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Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo,
New York 14263 (M.F.-P., D.L.K., S.V., J.M., C.W.P.) and
Department of
Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 (J.S.M., R.J.B.)
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.
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