Influence of spermidine on sister chromatid exchanges induced by alkylating agents in mammalian cells in vitro.

Sister chromatid exchanges (SCEs) are a very sensitive genetic end-point for in vitro identification of presumed carcinogenic and mutagenic agents, although the mechanism of their formation is still to be elucidated. The present work shows the influence of spermidine on SCE induction by two different DNA damaging agents: Mitomycin-C (MMC) and N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG). The SCE level induced by MMC was significantly decreased by spermidine. On the contrary, MNNG-induced SCEs were not affected. It has recently been suggested that MMC, via its reduced metabolite mitosene, produces bulky mono-and bi-adducts in DNA, mainly located in the minor groove of the double helix. MNNG, instead, directly methylates several electrophilic sites of DNA bases, such as the N7 and the O6 of guanines and the N3 of adenines. Both MMC and MNNG, despite their different mechanism of action, are potent SCE inducers. Spermidine, similarly to its structural analogue Spermine, is known to interact with DNA phosphate groups and to bind reversibly to the minor groove, thus stabilizing the double helix structure. Spermidine, being therefore ineffective on the MNNG-mediated DNA methylation, might affect DNA, making it structurally unavailable for MMC binding.