Effect of spermine synthase on the sensitivity of cells to anti-tumour agents

Abstract

The role of spermine in the sensitivity of cells to various established and experimental anti-tumour agents was examined, using paired cell lines that possess or lack spermine synthase. All spermine-synthase-deficient cells had no detectable spermine, and elevated spermidine, content. Spermine content did not alter the cell growth rate. There was little or no difference in sensitivity of immortalized mouse embryonic fibroblasts to doxorubicin, etoposide, cisplatin, methylglyoxal bis(guanylhydrazone) or H2O2 and only a slight increase in sensitivity to vinblastine and nocodazole. However, the absence of spermine clearly increased the sensitivity to 1,3-bis(2-chloroethyl)-N-nitrosourea, suggesting that depletion of spermine may be a useful way to increase the anti-neoplastic effects of anti-tumour agents that form chloroethyl-mediated interstrand DNA cross-links. The effects of spermine on the response to polyamine analogues (which have been proposed to be useful anti-neoplastic agents) were complex, and depended on the compound examined and on the cells tested. Sensitivity to CHENSpm {N1-ethyl-N11-[(cycloheptyl)methyl]-4,8-diazaundecane} was substantially greater in immortalized fibroblasts that lack spermine. In contrast, BE-3-4-3 [N1,N12-bis(ethyl)spermine] and BE-3-3-3 [N1,N11-bis(ethyl)norspermine] were more active against cells that contained spermine. The presence of spermine correlated with a greater induction of spermidine/spermine-N1-acetyltransferase by BE-3-3-3, which is consistent with suggestions that this induction is important for the response to this drug. These findings support the concepts that different polyamine analogues have different sites of action and that CHENSpm has a different site of action from BE-3-3-3.