Effects of the polyamine analogues BE-4-4-4-4, BE-3-7-3, and BE-3-3-3 on the proliferation of three prostate cancer cell lines.
OBJECTIVE
Polyamines are biologic cations necessary for normal cell growth. Polyamine analogues have been shown to be effective inhibitors of tumor growth. We tested the effect of the polyamine analogues 1,1 9-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4), N1,N11-bis(ethyl)norspermine (BE-3-3-3) and 1,15-bis(ethylamino)-4,12-diazapentadecane (BE-3-7-3) on the growth of the prostate cancer cell lines DU145, LNCaP and PC-3 in vitro. We also tested the effect of BE-4-4-4-4 on androgen-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 prostate cancer cell lines was inhibited in a dose-dependent manner by BE-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 growth which continued throughout the experiment with 74% (3 mg/kg) and 81% (5 mg/kg) growth inhibition seen on day 101. No overt toxic reactions besides weight loss were observed in BE-4-4-4-4-treated animals. Tumor tissue from animals treated with BE-4-4-4-4 showed a dose-dependent decrease in spermidine and spermine levels but no decline in putrescine 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 from animals treated at the 3 mg/kg and 5 mg/kg doses, respectively.


CONCLUSIONS
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 growth in vitro and BE-4-4-4-4 to be an effective inhibitor of DU145 cells in vivo with minimal toxicity.
Jeffers
L
L
Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison 53792-0001, USA.
Church
D
D
Basu
H
H
Marton
L
L
Wilding
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011073:Polyamines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011700:Putrescine / Q000032:analysis; D013095:Spermidine / Q000032:analysis; D013096:Spermine / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C106387:1,15-bis(ethylamino)-4,12-diazapentadecane; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D011073:Polyamines; D011437:Propylamines; C059685:N(1),N(11)-diethylnorspermine; C082768:BE 4-4-4-4; D013096:Spermine; D013095:Spermidine; D011700:Putrescine