Antitumor activity of the polyamine analog N(1), N(11)-diethylnorspermine against human prostate carcinoma cells.
BACKGROUND
Recent studies indicate that N-terminally bis-ethylated-polyamine 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 carcinoma cells was examined.


METHODS
The antiproliferative and biochemical effects of DENSpm were tested in four human prostate cancer cell lines, i.e., PC-3, TSU-pr1, DU-145, and JCA-1. The in vivo antitumor potential was explored in two groups of nude mice bearing small or more developed xenografts of the DU-145 cell line. The mice were treated with 40 mg/kg DENSpm, three times per day for two cycles of 6 days, on days 1-6 and 8-13.


RESULTS
In vitro studies showed that all four tested human prostate carcinoma cell lines were sensitive to DENSpm in micromolar concentrations. In tumor-bearing mice, DENSpm clearly prevented tumor growth in both size groups, which became significant after day 17. Treatment with DENSpm evoked intracellular accumulation of the analog and various regulatory responses, e.g., downregulation of the polyamine biosynthesis, the induction of the catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), and the depletion or decrease of natural polyamines. The cellular sensitivity to growth inhibition by DENSpm only correlated with the degree of ODC inhibition and SSAT induction.


CONCLUSIONS
DENSpm has sustained inhibitory effects on the growth of human prostate carcinoma cells in vitro as well in vivo. This polyamine analog may provide a new tool in the chemotherapy of prostate cancers with various phenotypes.
Schipper
R G
RG
Department of Pathology, University Medical Centre Nijmegen, The Netherlands.
Deli
G
G
Deloyer
P
P
Lange
W P
WP
Schalken
J A
JA
Verhofstad
A A
AA
D000123:Acetyltransferases / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine