BIOCHEMICAL AND GROWTH-MODULATORY EFFECTS OF THE NEW S-ADENOSYLMETHIONINE DECARBOXYLASE INHIBITOR CGP-48664 IN MALIGNANT AND IMMORTALIZED NORMAL HUMAN BREAST EPITHELIAL-CELLS IN CULTURE

CGP 48664 [4-aminoindanon-1-(2'-amidino)hydrazone dihydrochloride mono hydrate] is a newly introduced inhibitor of S-adenosylmethionine decar boxylase (SAMDC) with increased selectivity of action and reduced toxi city. We analyzed the biochemical and antiproliferative effects of thi s compound in a panel of hormone-dependent (3 clones of MCF-7, T47D) a nd -independent (MDA-MB-231, BT-20) human breast cancer cell lines in culture. Far comparison, we also tested its effects in the spontaneous ly immortalized human breast epithelial cell line MCF-10A. All cell li nes were highly sensitive to the growth-inhibitory effect of CGP 48664 with an IC50 between 0.1 and 0.5 mu M. A dose-dependent bell-shaped i ncrease in SAMDC was observed in normal and malignant breast cells res ulting from enzyme stabilization by the inhibitor as supported by West ern blot analysis. While ornithine decarboxylase (ODC) activity consis tently increased, the effect of CGP 48664 on spermidine/spermine N' ac etyltransferase (SSAT) was variable in the breast cancer cell lines. I n contrast, the inhibitor consistently reduced SSAT activity level in the MCF-10A cell line and its derivative partially transformed by a mu tated ras oncogene. As expected, cellular putrescine levels were marke dly increased by CGP 48664 administration, whereas spermidine and sper mine contents were reduced. However, the degree of reduction was usual ly only moderate. Furthermore, exogenous polyamine administration was relatively ineffective in rescuing the antiproliferative effect of CGP 48664 in MCF-7 cells, while exerting a more complete rescue in the MD A-MB-231 cell line. We conclude that CGP 48664 exerts a potent growth- inhibitory effect on mammary cells in culture. However, its action may not always be entirely mediated through the polyamine pathway. (C) 19 95 Wiley-Liss, Inc.