EFFECTS OF NOVEL SPERMINE ANALOGS ON CELL-CYCLE PROGRESSION AND APOPTOSIS IN MALME-3M HUMAN-MELANOMA CELLS

On the basis of encouraging preclinical findings, polyamine analogues have emerged as a novel class of experimental antitumor agents. The sp ermine derivative N-1,N-11-diethylnorspermine (DE-333, also known as D ENSPM) is currently undergoing Phase I clinical trials against solid t umors. A series of systematically modified DE-333 analogues differing in intra-amine carbon distances and in N-alkyl terminal substituents ( i.e., methyl, ethyl, and propyl) mere evaluated in MALME-3M human mela noma cells, a cell line known to be cytotoxically affected by DE-333 a nd especially responsive to analogue induction of the polyamine catabo lic enzyme spermidine/spermine N-1-acetyltransferase. Analogues accumu lated to comparable intracellular concentrations and similarly affecte d cell growth with IC50 values in the 0.5-1.0 mu m range. During prolo nged incubations, diethyl and dipropyl analogues were cytotoxic, where as two dimethyl analogues mere cytostatic. Cell cycle analysis followi ng treatment with the cytotoxic analogues revealed a prominent G(1) bl ock apparent as an accumulation of cells in G(0)/G(1) and depletion of S-phase cells as sell as a less restrictive G, block. By contrast, cy tostatic analogies incompletely arrested cells in G(1), leaving a sign ificant number of S-phase cells, Morphological and immunocytochemical analysis of detached cells revealed a far greater proportion of apopto tic cells with cytotoxic analogues than with cytostatic analogues, Alt hough spermidine/spermine N-1-acetyltransferase activity was different ially induced by the analogues, there was no obvious correlation with cell cycle effects. Overall, these data indicate a previously unrecogn ized combined effect of polyamine analogues on cell cycle progression and apoptosis. On the basis of structure-function relationships, these activities may be manipulated to optimize therapeutic efficacy.