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

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...

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Veröffentlicht in:BJU international 2006-02, Vol.97 (2), p.404-409
Hauptverfasser: HELENIUS, MERJA A., SAVINAINEN, KIMMO J., BOVA, G. STEVEN, VISAKORPI, TAPIO
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creator HELENIUS, MERJA A.
SAVINAINEN, KIMMO J.
BOVA, G. STEVEN
VISAKORPI, TAPIO
description 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.
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STEVEN ; VISAKORPI, TAPIO</creator><creatorcontrib>HELENIUS, MERJA A. ; SAVINAINEN, KIMMO J. ; BOVA, G. STEVEN ; VISAKORPI, TAPIO</creatorcontrib><description>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.</description><identifier>ISSN: 1464-4096</identifier><identifier>EISSN: 1464-410X</identifier><identifier>DOI: 10.1111/j.1464-410X.2005.05912.x</identifier><identifier>PMID: 16430655</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Amiloride - therapeutic use ; Antineoplastic agents ; Biological and medical sciences ; Blood Proteins - therapeutic use ; gene amplification ; Gene Amplification - genetics ; General aspects ; Humans ; In Situ Hybridization, Fluorescence - methods ; Male ; Medical sciences ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - genetics ; Neoplasms, Hormone-Dependent - drug therapy ; Neoplasms, Hormone-Dependent - genetics ; Nephrology. Urinary tract diseases ; Pharmacology. Drug treatments ; PLAU ; prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Reverse Transcriptase Polymerase Chain Reaction - methods ; Sensitivity and Specificity ; Tumors of the urinary system ; Urinary tract. 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STEVEN</creatorcontrib><creatorcontrib>VISAKORPI, TAPIO</creatorcontrib><title>Amplification of the urokinase gene and the sensitivity of prostate cancer cells to urokinase inhibitors</title><title>BJU international</title><addtitle>BJU Int</addtitle><description>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.</description><subject>Amiloride - therapeutic use</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Blood Proteins - therapeutic use</subject><subject>gene amplification</subject><subject>Gene Amplification - genetics</subject><subject>General aspects</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence - methods</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Neoplasms, Hormone-Dependent - drug therapy</subject><subject>Neoplasms, Hormone-Dependent - genetics</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Pharmacology. Drug treatments</subject><subject>PLAU</subject><subject>prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction - methods</subject><subject>Sensitivity and Specificity</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><subject>urokinase</subject><subject>Urokinase-Type Plasminogen Activator - genetics</subject><issn>1464-4096</issn><issn>1464-410X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1PwyAYxonRuPnxLxguemsFWmg5eJiLn1niZSbeCKXgmF07C9Ptv5du03lTQsIb-D3w8LwAQIxiHMblNMYpS6MUo5eYIERjRDkm8XIP9H8O9r9rxFkPHDk3RShsMHoIepilCWKU9sFkMJtX1lglvW1q2BjoJxou2ubN1tJp-KprDWVdrredrp319sP6VUfO28Z56TVUsla6hUpXlYO--SW39cQW1jetOwEHRlZOn27XYzC-vRkP76PR093DcDCKVEpyEmHCWZKUJLgzJi0UN3lWqNJkRU45MoRpwwk3GJWIJygjiubMsCQzWYkLipNjcLG5Nph7X2jnxcy6zpisdbNwIgsaTDLyJ0hQnmKe5AHMN6AK33WtNmLe2plsVwIj0XVDTEUXtOhCF103xLobYhmkZ9s3FsVMlzvhNv4AnG8B6ZSsTBuCtG7HZZSFyQJ3teE-baVX_zYgrh-fuyr5At4OpqI</recordid><startdate>200602</startdate><enddate>200602</enddate><creator>HELENIUS, MERJA A.</creator><creator>SAVINAINEN, KIMMO J.</creator><creator>BOVA, G. 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STEVEN ; VISAKORPI, TAPIO</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4282-129633d2065ff4bc9f87bcdf7b8590f26ef929f10d093072c586f637f7d1b513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amiloride - therapeutic use</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Blood Proteins - therapeutic use</topic><topic>gene amplification</topic><topic>Gene Amplification - genetics</topic><topic>General aspects</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence - methods</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasms, Hormone-Dependent - drug therapy</topic><topic>Neoplasms, Hormone-Dependent - genetics</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Pharmacology. Drug treatments</topic><topic>PLAU</topic><topic>prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction - methods</topic><topic>Sensitivity and Specificity</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><topic>urokinase</topic><topic>Urokinase-Type Plasminogen Activator - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HELENIUS, MERJA A.</creatorcontrib><creatorcontrib>SAVINAINEN, KIMMO J.</creatorcontrib><creatorcontrib>BOVA, G. 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STEVEN</au><au>VISAKORPI, TAPIO</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amplification of the urokinase gene and the sensitivity of prostate cancer cells to urokinase inhibitors</atitle><jtitle>BJU international</jtitle><addtitle>BJU Int</addtitle><date>2006-02</date><risdate>2006</risdate><volume>97</volume><issue>2</issue><spage>404</spage><epage>409</epage><pages>404-409</pages><issn>1464-4096</issn><eissn>1464-410X</eissn><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.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>16430655</pmid><doi>10.1111/j.1464-410X.2005.05912.x</doi><tpages>6</tpages></addata></record>
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subjects Amiloride - therapeutic use
Antineoplastic agents
Biological and medical sciences
Blood Proteins - therapeutic use
gene amplification
Gene Amplification - genetics
General aspects
Humans
In Situ Hybridization, Fluorescence - methods
Male
Medical sciences
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - genetics
Neoplasms, Hormone-Dependent - drug therapy
Neoplasms, Hormone-Dependent - genetics
Nephrology. Urinary tract diseases
Pharmacology. Drug treatments
PLAU
prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Reverse Transcriptase Polymerase Chain Reaction - methods
Sensitivity and Specificity
Tumors of the urinary system
Urinary tract. Prostate gland
urokinase
Urokinase-Type Plasminogen Activator - genetics
title Amplification of the urokinase gene and the sensitivity of prostate cancer cells to urokinase inhibitors
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