POLYAMINE ANALOG INDUCTION OF PROGRAMMED CELL-DEATH IN HUMAN LUNG-TUMOR CELLS

The naturally occurring polyamines putrescine, spermidine, and spermin e are required for cell growth. Based on this requirement, several pol yamine analogues that interfere with polyamine function and metabolism have been synthesized as antineoplastic agents. The symmetrically sub stituted N-1,N-12-bis(ethyl)spermine (BESpm), and unsymmetrically subs tituted ethyl-N-11-[(cyclopropyl)methyl]-4,8-diazaundecane (CPENSpm) h ave previously been shown to cause rapid cytotoxicity of NCI H157 cell s, with concurrent high induction of the polyamine catabolic enzyme sp ermidine/spermine N-1-acetyltransferase. However, the precise mechanis m(s) of the cytotoxic action of the compounds is not known. We now dem onstrate that treatment with either BESpm or CPENSpm results in morpho logical and biochemical changes consistent with the activation of prog rammed cell death pathways, and that the unsymmetrically substituted C PENSpm more rapidly activates the death program. These studies suggest that the cell type-specific cytotoxicity of these polyamine analogues may be a result of their ability to selectively activate the cell dea th pathway in sensitive phenotypes and indicate that the relationship between the structure of the polyamine analogues and the ability to in duce programmed cell death should be investigated.