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


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.


CONCLUSIONS
These results suggest that selective inhibition of the uPA pathway in individuals whose tumours contain uPA gene amplification may provide therapeutic benefit.
Helenius
Merja A
MA
Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere, Tampere University Hospital, Tampere, Finland.
Savinainen
Kimmo J
KJ
Bova
G Steven
GS
Visakorpi
Tapio
T
D000584:Amiloride / Q000627:therapeutic use*; D001798:Blood Proteins / Q000627:therapeutic use*; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D001798:Blood Proteins; C031220:urokinase inhibitor; D000584:Amiloride; D014568:Urokinase-Type Plasminogen Activator