Human prostatic carcinoma cell lines display altered regulation of polyamine transport in response to polyamine analogs and inhibitors.
BACKGROUND
The possibility was investigated that complex homeostatic mechanisms which maintain polyamine pools in prostate-derived tumors may differ from those which are typically seen in other tissues and tumors.


METHODS
Growth sensitivity and various regulatory responses were investigated in three human prostate carcinoma cell lines (LNCaP, DU145, and PC-3) treated with the inhibitor of S-adenosylmethionine decarboxylase CGP-48664 or the polyamine analog N1,N11-diethylnorspermine (DENSPM), both of which are currently undergoing phase I clinical trial.


RESULTS
Prostate tumor cell lines were all similarly growth-inhibited by the inhibitor CGP-48664 (IC50 values, 1-5 microM at 72 hr), but varied considerably in their sensitivity to DENSPM. The rank-order for cell-line growth inhibition by the analog was DU145 > PC-3 > LNCaP, with IC50 values of 1, 30, and 1,000 microM, respectively. Both compounds depleted intracellular polyamine pools to levels which seemed sufficient to account for inhibition of cell growth. While polyamine enzyme regulatory responses to both CGP-48664 and DENSPM were typical of those seen in other cell types, regulation of polyamine transport differed distinctly. Based on Vmax determinations, LNCaP cells failed to upregulate transport in response to CGP-48664, while PC-3 and LNCaP cells failed to downregulate transport in response to DENSPM.


CONCLUSIONS
Relative to other cell lines, polyamine transport in prostate carcinoma cell lines was found to be uniquely insensitive to regulation by polyamines or analogs. Although this did not seem to correlate with growth sensitivity to polyamine analogs in vitro, it should be therapeutically exploitable in in vivo systems.
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Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kramer
D L
DL
Miller
J T
JT
Bergeron
R J
RJ
Bernacki
R
R
Porter
C W
CW
D012437:Adenosylmethionine Decarboxylase / Q000494:pharmacology*; D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011073:Polyamines / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism*
D000578:Amidines; D006131:Growth Inhibitors; D007189:Indans; D011073:Polyamines; C059685:N(1),N(11)-diethylnorspermine; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D013096:Spermine; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine