EFFECTS OF A BIS(BENZYL)SPERMINE ANALOG ON MCF-7 BREAST-CANCER CELLS IN CULTURE AND NUDE-MICE XENOGRAFTS

We studied the effects of a polyamine analog, {3-[(phenylmethyl)amino] propyl}-1,7-diaminoheptane (MDL 27695) on MCF-7 cells, as part of an a ttempt to develop new drugs for breast cancer treatment. Using [H-3]-t hymidine incorporation assay and long-term growth curves, we found tha t MDL 27695 inhibited the growth of MCF-7 cells in a dose-dependent ma nner in the low mu M range. G1 synchronized cells progressing in cell cycle showed delayed and inefficient entry into S phase in the presenc e of 4 mu M MDL 27695. Consistent with a G1 arrest, MDL 27695 signific antly reduced estradiol-mediated increase in the expression of cyclin D1. HPLC analysis showed that treatment of MCF-7 cells with MDL 27695 reduced the accumulation of natural polyamines, putrescine, spermidine , and spermine, by 43, 38, and 45%, respectively, at 8 h after the ini tiation of cell cycle. This decrease in polyamine levels was not assoc iated with a decrease in the activity of polyamine biosynthetic (ornit hine decarboxylase, ODC; s-adenosylmethionine decarboxylase, SAMDC) or catabolizing (spermidine/spermine acetyltransferase, SSAT) enzymes. H owever, there was a 40% decrease in the uptake of putrescine and sperm idine, in cells treated with MDL 27695. Our studies also showed that M DL 27695, at a dose of 20 mg/kg, caused a significant inhibition of tu mor growth in nude mice harboring MCF-7 cell derived tumors, without o vert symptoms of toxicity. These data indicate that the polyamine anal og MDL 27695 is an efficient inhibitor of MCF-7 breast cancer cell gro wth in vitro and in vivo. Our results suggest that polyamines are crit ical factors in cell cycle regulation of breast cancer cells and poten tial targets for therapy.