EFFECTS OF THE POLYAMINE ANALOGS BE-4-4-4-4, BE-3-7-3, AND BE-3-3-3 ON THE PROLIFERATION OF 3 PROSTATE-CANCER CELL-LINES

Purpose: Polyamines are biologic cations necessary for normal cell gro wth. Polyamine analogues have been shown to be effective inhibitors of tumor growth. We tested the effect of the polyamine analogues 1,19-bi s(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4), N-1,N-11-bis(ethy l)norspermine (BE-3-3-3) and 1,15-bis(ethylamino)-4,12-diazapentadecan e (BE-3-7-3) on the growth of the prostate cancer cell lines DU145, LN CaP and PC-3 in vitro. We also tested the effect of BE-4-4-4-4 on andr ogen-independent DU145 cells in vivo via a nude mouse xenograft model. Methods: In vitro, cell proliferation was measured using a DNA assay or a colony-formation assay. In vivo, mice were given saline or BE-4-4 -4-4 3 mg/kg or 5 mg/kg intraperitoneally twice daily on days 7-10 and 14-17 (cycle 1), days 49-52 and 56-59 (cycle 2) and days 91-94 and 98 -101 (cycle 3). Results: The proliferation of DU145, LNCaP and PC-3 pr ostate cancer cell lines was inhibited in a dose-dependent manner by B E-4-4-4-4. Intracellular putrescine, spermidine and spermine levels in all three cell lines declined after only 24 h exposure to BE-4-4-4-4 in vitro. Animals receiving BE-4-4-4-4 showed inhibition of tumor grow th which continued throughout the experiment with 74% (3 mg/kg) and 81 % (5 mg/kg) growth inhibition seen on day 101, No overt toxic reaction s besides weight loss were observed in BE-4-4-4-4-treated animals. Tum or tissue from animals treated with BE-4-4-4-4 showed a dose-dependent decrease in spermidine and spermine levels but no decline in putresci ne levels as compared with control. BE-4-4-4-4 levels were highest in tumors on day 63 with levels reaching 0.33 and 1.45 nmol/mg protein fr om animals treated at the 3 mg/kg and 5 mg/kg doses, respectively. Con clusion: These results show the polyamine analogues BE-4-4-4-4, BE-3-3 -3 and BE-3-7-3 to be effective inhibitors of prostate cancer cell gro wth in vitro and BE-4-4-4-4 to be an effective inhibitor of DU145 cell s in vivo with minimal toxicity.