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 m ay differ from those which are typically seen in other tissues and tum ors. METHODS. Growth sensitivity and various regulatory responses were investigated in three human prostate carcinoma cell lines (LNCaP, DU1 45, and PC-3) treated with the inhibitor of S-adenosylmethionine decar boxylase CGP-48664 or the polyamine analog N-1,N-11-diethylnorspermine DENSPM), both of which are currently undergoing phase I clinical tria l. RESULTS. Prostate tumor cell lines were all similarly growth-inhibi ted by the inhibitor CGP-48664 (IC50 values, 1-5 mu M at 72 hr), but v aried considerably in their sensitivity to DENSPM. The rank-order for cell-line growth inhibition by the analog was DU145 > PC-3 > LNCaP, wi th IC50 values of 1, 30, and 1,000 mu M, respectively. Both compounds depleted intracellular polyamine pools to levels which seemed sufficie nt to account for inhibition of cell growth. While polyamine enzyme re gulatory responses to both CGP-48664 and DENSPM were typical of those seen in other cell types, regulation of polyamine transport differed d istinctly. Based on V-max determinations, LNCaP cells failed to upregu late transport in response to CGP-48664, while PC-3 and LNCaP cells fa iled to downregulate transport in response to DENSPM. CONCLUSIONS. Rel ative to other cell lines, polyamine transport in prostate carcinoma c ell lines was found to be uniquely insensitive to regulation by polyam ines or analogs. Although this did not seem to correlate with growth s ensitivity to polyamine analogs in vitro, it should be therapeutically exploitable in in vivo systems. (C) 1998 Wiley-Liss, Inc.