Role of ornithine decarboxylase suppression and polyamine depletion in the antiproliferative activity of polyamine analogs.
Two transfected cell lines, one carrying a mammalian ornithine decarboxylase (ODC) that is suppressed by polyamines and one carrying a trypanosomal ODC that is not, were used to ask whether ODC suppression is necessary for the antiproliferative activities of two polyamine analogs, N1,N8-bis(ethyl)spermidine (BES) and N1,N14-bis(ethyl)homospermine (BE444). Both analogs accumulated within cells and suppressed S-adenosylmethionine decarboxylase, as well as polyamine-sensitive mouse ODC activity. Neither drug was able to suppress the activity of the polyamine-refractory trypanosome ODC. But, whereas BE444 was able to inhibit growth of both cell lines, BES could inhibit only growth of cells carrying the polyamine-sensitive ODC, under conditions that cause prolonged depletion of endogenous polyamines. We conclude from these studies that the antiproliferative activity of BES, a less potent drug, requires the suppression of ODC. The efficacy of BE444 is enhanced by its ability to suppress ODC. However, it can function without ODC suppression, whereas BES cannot.
Ghoda
L
L
Department of Microbiology and Immunology, School of Medicine, University of California, San Francisco 94143.
Basu
H S
HS
Porter
C W
CW
Marton
L J
LJ
Coffino
P
P
D012437:Adenosylmethionine Decarboxylase / Q000187:drug effects; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D009955:Ornithine Decarboxylase / Q000187:drug effects / Q000502:physiology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D013095:Spermidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D014345:Trypanosoma / Q000201:enzymology
D015317:Biogenic Polyamines; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C058306:N(1),N(14)-bis(ethyl)homospermine; D013096:Spermine; C050659:N(1),N(8)-diethylspermidine; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine