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.

Abstract

PURPOSE:

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.

CONCLUSION:

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.

• Authors: L Jeffers, D Church, H Basu, L Marton, G Wilding
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 40 Issue 2 Pg. 172-9 ( 1997) ISSN: 0344-5704 [Print] Germany
• PMID: 9182840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,15-bis(ethylamino)-4,12-diazapentadecane
• Antineoplastic Agents
• Growth Inhibitors
• Polyamines
• Propylamines
• N(1),N(11)-diethylnorspermine
• BE 4-4-4-4
• Spermine
• Spermidine
• Putrescine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Division (drug effects)
• Growth Inhibitors (pharmacology)
• Male
• Mice
• Mice, Nude
• Polyamines (pharmacology)
• Propylamines (pharmacology)
• Prostatic Neoplasms (pathology)
• Putrescine (analysis)
• Spermidine (analysis)
• Spermine (analogs & derivatives, analysis, pharmacology)
• Tumor Cells, Cultured