title: Effects of a bis(benzyl)spermine analog on MCF-7 breast cancer cells in culture and nude mice xenografts.
abstract: We studied the effects of a polyamine analog, N,N'-bis{3-[(phenylmethyl)amino]propyl}-1,7-diaminoheptane (MDL 27695) on MCF-7 cells, as part of an attempt to develop new drugs for breast cancer treatment. Using [H-3]-thymidine incorporation assay and long-term growth curves, we found that MDL 27695 inhibited the growth of MCF-7 cells in a dose-dependent manner in the low mu M range. G1 synchronized cells progressing in cell cycle showed delayed and inefficient entry into S phase in the presence of 4 mu M MDL 27695. Consistent with a G1 arrest, MDL 27695 significantly 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 initiation of cell cycle. This decrease in polyamine levels was not associated with a decrease in the activity of polyamine biosynthetic (ornithine decarboxylase, ODC; s-adenosylmethionine decarboxylase, SAMDC) or catabolizing (spermidine/spermine acetyltransferase, SSAT) enzymes. However, there was a 40% decrease in the uptake of putrescine and spermidine, in cells treated with MDL 27695. Our studies also showed that MDL 27695, at a dose of 20 mg/kg, caused a significant inhibition of tumor growth in nude mice harboring MCF-7 cell derived tumors, without overt symptoms of toxicity. These data indicate that the polyamine analog MDL 27695 is an efficient inhibitor of MCF-7 breast cancer cell growth in vitro and in vivo. Our results suggest that polyamines are critical factors in cell cycle regulation of breast cancer cells and potential targets for therapy.
authors: UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT MED,NEW BRUNSWICK,NJ 08903. UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT ENVIRONM & COMMUNITY MED,NEW BRUNSWICK,NJ 08903. UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,CANC INST NEW JERSEY,NEW BRUNSWICK,NJ 08903. RUTGERS STATE UNIV,DEPT PHARMACOL & TOXICOL,PISCATAWAY,NJ 08854. PENN STATE UNIV,MILTON S HERSHEY MED CTR,DEPT OBSTET & GYNECOL,HERSHEY,PA 17033.
authors: T
authors: T
authors: Thomas
authors: N
authors: N
authors: Shah
authors: C
authors: C
authors: Faaland
authors: M
authors: M
authors: Gallo
authors: E
authors: E
authors: Yurkow
authors: P
authors: P
authors: Satyaswaroop