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Effects of a bis(benzyl)spermine analog on MCF-7 breast cancer cells in culture and nude mice xenografts

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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.
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Document Type: Research Article

Affiliations: 1: 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. 2: 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.

Publication date: January 1, 1997

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