THE ROLE OF POLYAMINE CATABOLISM IN POLYAMINE ANALOG-INDUCED PROGRAMMED CELL-DEATH

thyl-N-11-[(cyclopropyl)methyl]-4,8,-diazaundecane (CPENSpm) is a poly amine analogue that represents a ne rv class of antitumor agents that demonstrate phenotype-specific cytotoxic activity, However, the precis e mechanism of its selective cytotoxic activity is not known. CPENSpm treatment results in the superinduction of the polyamine catabolic enz yme spermidine/spermine N-1-acetyltransferase (SSAT) in sensitive cell types and has been demonstrated to induce programmed cell death (PCD) , The catalysis of polyamines by the SSAT/polyamine oxidase (PAO) path way produces H2O2 as one product, suggesting that PCD produced by CPEN Spm may be, in part, due to oxidative stress as a result of H2O2 produ ction. In the sensitive human nonsmall cell line H157, the coaddition of catalase significantly reduces high molecular weight (HMW) DNA (gre ater than or equal to 50 kb) and nuclear fragmentation, Important to n ote, specific inhibition of PAO by N,N'-bis(2,3-butadienyl)-1,4-butane -diamine results in a significant reduction of the formation of HMW DN A and nuclear fragmentation, In contrast, the coaddition of catalase o r PAO inhibitor has no effect on reducing HMW DNA fragmentation induce d by N-1-ethyl-N-11-(cycloheptyl)methyl] 4,8,-diazaundecane, which doe s not induce SSAT and does not deplete intracellular polyamines. These results strongly suggest that H2O2 production by PAO has a role in CP ENSpm cytotoxicity in sensitive cells via PCD and demonstrate a potent ial basis for differential sensitivity to this promising new class of antineoplastic agents, Furthermore, the data suggest a general mechani sm by which, under certain stimuli, cells can commit suicide through c atabolism of the ubiquitous intracellular polyamines.