Effects of diethyl spermine analogues in human bladder cancer cell lines in culture.
The biochemical and antiproliferative effects of two recently developed N-alkylated analogues of naturally-occurring polyamines, N1,N14-diethylhomospermine (DEHSPM) and N1,N11-diethylnorspermine (DENSPM), were investigated in two human transitional cell carcinoma (TCC) lines, T24 and J82. Parallel studies with the ornithine decarboxylase enzyme inhibitor alpha-difluoromethylornithine (DFMO) were included for comparison. DENSPM displayed greater antiproliferative activity than DEHSPM in both TCC cell lines. Both analogues were strikingly more potent than DFMO. DEHSPM and DENSPM suppressed the activity of the major biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase. However, differences in the resulting polyamine depletion suggest that the substantial antiproliferative activity of these analogues may result from mechanisms other than polyamine depletion. The greater polyamine depletion seen with DENSPM is thought to result from its striking induction of spermidine/spermine N1-acetyltransferase. DENSPM is an attractive agent for further preclinical and clinical development, possibly as a chemopreventive agent, in TCC of the bladder.
Medical Research Service, Augusta VA Medical Center, Georgia 30904-6285.
B K
BK
Chang
Y
Y
Liang
D W
DW
Miller
R J
RJ
Bergeron
C W
CW
Porter
G
G
Wang
D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D000518:Eflornithine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
C058306:N(1),N(14)-bis(ethyl)homospermine; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine; D000518:Eflornithine