Antitumor activity of the polyamine analog N-I,N-II-diethylnorspermine against human prostate carcinoma cells

BACKGROUND. Recent studies indicate that N-terminally bis-ethylated-polyami ne analogs have significant antitumor activity in several human solid-tumor models. In this study, the in vitro and in vivo antitumor potential of the polyamine analog N-1,N-11-diethylnorspermine (DENSpm) in human prostate ca rcinoma cells was examined. METHODS. The antiproliferative and biochemical effects of DENSpm were teste d in four human prostate cancer cell lines, i.e., PC-3, TSU-pr1, DU-145, an d JCA-1. The in vivo antitumor potential was explored in two soups of nude mice bearing small or more developed xenografts of the DU-145 cell line. Th e mice were treated with 40 mg/kg DENSpm, three times per day for two cycle s of 6 days, on days 1-6 and 8-13. RESULTS. In vitro studies showed that all four tested human prostate carcin oma cell lines were sensitive to DENSpm in micromolar concentrations. in tu mor-bearing mice, DENSpm clearly prevented tumor growth in both size groups , which became significant after day 17. Treatment with DENSpm evoked intra cellular accumulation of the analog and various regulatory responses, e.g., downregulation of the polyamine biosynthesis, the induction of the catabol ic enzyme spermidine/spermine N-1-acetyltransferase (SSAT), and the depleti on or decrease of natural polyamines, The cellular sensitivity to growth in hibition by DENSpm only correlated with the degree of ODC inhibition and SS AT induction. CONCLUSIONS. DENSpm has sustained inhibitory effects on the growth of human prostate carcinoma cells in vitro as well in vivo. This polyamine analog m ay provide a new tool in the chemotherapy of prostate cancers with various phenotypes. (C) 2000 Wiley-Liss, Inc.