title: Effects of novel spermine analogues on cell cycle progression and apoptosis in MALME-3M human melanoma cells.
abstract: On the basis of encouraging preclinical findings, polyamine analogues have emerged as a novel class of experimental antitumor agents. The spermine derivative N1,N11-diethylnorspermine (DE-333, also known as DENSPM) is currently undergoing Phase I clinical trials against solid tumors. 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) were evaluated in MALME-3M human melanoma cells, a cell line known to be cytotoxically affected by DE-333 and especially responsive to analogue induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. Analogues accumulated to comparable intracellular concentrations and similarly affected cell growth with IC50 values in the 0.5-1.0 microM range. During prolonged incubations, diethyl and dipropyl analogues were cytotoxic, whereas two dimethyl analogues were cytostatic. Cell cycle analysis following treatment with the cytotoxic analogues revealed a prominent G1 block apparent as an accumulation of cells in G0/G1 and depletion of S-phase cells as well as a less restrictive G2 block. By contrast, cytostatic analogues incompletely arrested cells in G1, leaving a significant number of S-phase cells. Morphological and immunocytochemical analysis of detached cells revealed a far greater proportion of apoptotic cells with cytotoxic analogues than with cytostatic analogues. Although spermidine/spermine N1-acetyltransferase activity was differentially induced by the analogues, there was no obvious correlation with cell cycle effects. Overall, these data indicate a previously unrecognized 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.
authors.affiliation: Grace Cancer Drug Center, Roswell Park Cancer Center, Buffalo, New York 14263, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Kramer
authors.forename: M
authors.initials: M
authors.lastname: Fogel-Petrovic
authors.forename: P
authors.initials: P
authors.lastname: Diegelman
authors.forename: J M
authors.initials: JM
authors.lastname: Cooley
authors.forename: R J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: J S
authors.initials: JS
authors.lastname: McManis
authors.forename: R J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: C W
authors.initials: CW
authors.lastname: Porter
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015317:Biogenic Polyamines / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D013096:Spermine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine