STRUCTURAL BASIS FOR DIFFERENTIAL INDUCTION OF SPERMIDINE SPERMINE N-1-ACETYLTRANSFERASE ACTIVITY BY NOVEL SPERMINE ANALOGS/

The spermine analog N-1,N-11 -diethylnorspermine (DE-333, also known a s DENSPM or BENSPM) is regarded as the most potent known inducer of th e polyamine catabolic enzyme, spermidine/spermine N-1-acetyltransferas e (SSAT), increasing activity by more than 200- to 1000-fold in certai n cell types. The relative ability of a series of eight systematically modified DE-333 analogs to affect SSAT expression was examined in Mal me-3M human melanoma cells, one of several cell lines known to be espe cially responsive to induction of this enzyme. In particular, we exami ned the relative contribution of induction of enzyme mRNA and prolonga tion of enzyme half-life to analog-mediated increases in enzyme activi ty. 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 determ ined by the terminal N-alkyl substituent size; among methyl, ethyl and propyl groups, methyl was least effective. Thus, DE-333, which most p otently induces SSAT mRNA and effectively stabilizes SSAT enzyme activ ity, produces the greatest increase in enzyme activity. Although other contributing mechanisms may be involved, the relative abilities of th e various analogs to induce enzyme activity is at least partially attr ibutable to their combined effects on enzyme mRNA and protein half-lif e. These data reveal the highly sensitive structure-activity relations hips that underlie and control spermine analog induction of SSAT activ ity. Pending further definition of the relationship between SSAT induc tion and antitumor growth and toxicity in vivo, these relationships ma y be used to optimize therapeutic efficacy.