Effect of three novel polyamine oxa-analogues (MTR-OSPD, DIP-SPN and APPO-TFA) on the growth and proliferation of Swiss 3T3 cells.
In order to investigate their biological function on cellular polyamine content, cell growth and proliferation, three novel polyamine oxa-analogues, 5-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-6-oxa-spermidine (MTR-OSPD); 6,9-dioxa-5,10-di-(2,2,5,7,8-pentamethylchroman-6-sulfonyl) spermine (DIP-SPN) and 3-aminopropyl N-(3-phthalimidopropyloxy) trifluoroacetimidate (APPO-TFA) were tested for their ability to stop or slow down the growth of Swiss 3T3 cells. Cells at 50-60% confluency were grown for 24 or 48 hr in the presence of a wide range of polyamine oxa-analogue concentrations and the number of cells counted. To determine whether the drugs were cytotoxic or cytostatic, the analogue-containing medium in some vials was replaced with fresh culture medium after 48 hr and the cells incubated for a further 24 hr. Cellular protein, RNA, DNA, polyamine contents and the activities of ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase and spermidine/spermine N1-acetyltransferase were also determined at the lowest effective analogue concentration. All three inhibitors stopped cell proliferation at concentrations over 100 microM. Both MTR-OSPD and DIP-SPN were cytotoxic, since the cells could not be revived by removing the inhibitor from the medium, whereas APPO-TFA was only cytostatic. At the lowest effective concentration the analogues had little effect on protein, RNA and DNA content of the cells, but had varying effects on polyamine metabolism. The most interesting analogue was APPO-TFA. This drug showed concentration-dependent growth inhibition between concentrations of 5 nM and 5 microM. These novel analogues may be of value in elucidating the precise functions of polyamines in cellular metabolism. Their exact mode of action is now under investigation.
Bardocz
S
S
BORC, Rowett Research Institute, Bucksburn, Aberdeen, U.K.
Sakhri
M
M
Pusztai
A
A
Maguire
N M
NM
Lin
P K
PK
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004247:DNA / Q000032:analysis; D007097:Imines / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010797:Phthalimides / Q000494:pharmacology*; D012313:RNA / Q000032:analysis; D013095:Spermidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*
C100009:3-aminopropyl N-(3-phthalimidopropyloxy)trifluoroacetimidate; C100005:5-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-6-oxaspermidine; C100007:6,9-dioxa-5,10-di-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)spermine; D002839:Chromans; D007097:Imines; D010797:Phthalimides; D013449:Sulfonamides; D013096:Spermine; D012313:RNA; D004247:DNA; D013095:Spermidine