Effect of the polyamine oxidase inactivator MDL 72527 on N-1-(n-octanesulfonyl)spermine toxicity

N-1-(n-octanesulfonyl)spermine (N(1)OSSpm) is a potent calmodulin antagonis t. In the present work, its toxicity to DHD/K12/TRb and CaCo-2 cells, two c olon carcinoma-derived cell lines, was studied with the aim to identify tho se properties of the cells, which determine their sensitivity to N(1)OSSpm and related structures. Exposure of the cells to MDL 72527, a compound cons idered to be a selective inactivator of polyamine oxidase (PAO) increased t he cytotoxicity of N(1)OSSpm to both cell lines. In contrast, toxicity of t rifluoperazine, a calmodulin antagonist with a polyamine-unrelated structur e, was not enhanced by MDL 72527. Combined exposure of cells to 2-(difluoro methyl)ornithine (DFMO) (a selective inactivator of ornithine decarboxylase ), MDL 72527 and N(1)OSSpm produced a synergistic cytotoxic effect. Neither the intrinsic PAO activity of the cells (as determined with N-1,N-12-diace tylspermine as substrate), nor their ability to accumulate the drug was a d eterminant of the cytotoxic effect of N(1)OSSpm. These data suggest that MD L 72527 has a target unrelated to PAO; which is responsible for the enhance ment of N(1)OSSpm (and spermine) toxicity. Identification of this target ma y be of use if the therapeutic potentials of MDL 72527 are to be exploited. (C) 2000 Elsevier Science Ltd. All rights reserved.