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Effects of Novel Spermine Analogues on Cell Cycle Progression and Apoptosis in MALME-3M Human Melanoma Cells¹

Grace Cancer Drug Center, Roswell Park Cancer Center, Buffalo, New York 14263 [D. L. K., M. F-P., P. D., J. M. C., R. J. Bern., C. W. P.], and Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Center, Gainesville, Florida 32610 [R. J. Berg., J. S. M.]

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 µM 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.

¹ This work was supported in part by National Cancer Institute Grants CA37606, CA16056, and CA13038 (NIH, United States Department of Health and Human Services).

² To whom requests for reprints should be addressed, at Grace Cancer Drug Center, Roswell Park Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: porter@sc3101.med.buffalo.edu.

Received 5/19/97. Accepted 10/14/97.

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