Amplification of the urokinase gene and the sensitivity of prostate cancer cells to urokinase inhibitors.

Abstract

OBJECTIVES:

To evaluate the frequency of the urokinase-type plasminogen activator (uPA) gene amplification and the sensitivity of prostate cancer cells to uPA inhibition, as we previously found one hormone-refractory prostate tumour with high-level amplification of the uPA (alias PLAU) gene, and also showed that a uPA inhibitor, amiloride, can effectively reduce the invasion potential of the PC-3 prostate cancer cell line.

MATERIALS AND METHODS:

Sixty-three locally recurrent hormone-refractory tumours and 78 hormone-refractory metastases from 29 patients who died from prostate cancer were analysed for uPA gene-copy number using fluorescence in situ hybridization. The Matrigel invasion assay was used to study the influence of uPA inhibitors on the invasive potential of prostate cancer cell lines.

RESULTS:

Of the locally recurrent hormone-refractory tumours, 21% had an increased copy number of uPA, but no high-level amplifications were found; 31% of the metastases had increased copy number and one high-level amplification of the uPA. Matrigel invasion assays with two specific uPA inhibitors, B428 and p-aminobenzamidine, showed that invasion of a prostate cancer cell line containing uPA gene amplification was inhibited by these small-molecule uPA inhibitors, while invasion of prostate cell lines without uPA gene amplification were not.

CONCLUSION:

These results suggest that selective inhibition of the uPA pathway in individuals whose tumours contain uPA gene amplification may provide therapeutic benefit.

• Authors: Merja A Helenius, Kimmo J Savinainen, G Steven Bova, Tapio Visakorpi
• Journal: BJU international (BJU Int) Vol. 97 Issue 2 Pg. 404-9 (Feb 2006) ISSN: 1464-4096 [Print] England
• PMID: 16430655 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Proteins
• urokinase inhibitor
• Amiloride
• Urokinase-Type Plasminogen Activator

Topics

• Amiloride (therapeutic use)
• Blood Proteins (therapeutic use)
• Gene Amplification (genetics)
• Humans
• In Situ Hybridization, Fluorescence (methods)
• Male
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Neoplasms, Hormone-Dependent (drug therapy, genetics)
• Prostatic Neoplasms (drug therapy, genetics)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Sensitivity and Specificity
• Urokinase-Type Plasminogen Activator (genetics)