Doi:10.1016/s1569-9056(08)60827-

INTERMITTENT DHT ADMINISTRATION ENHANCES EFFECT OF
INVOLVEMENT OF THE ESTROGEN RECEPTOR˟ IN GENISTEIN-
DOCETAXEL IN A XENOGRAFT MODEL BY MODULATION OF ER˟,
INDUCED EXPRESSION OF P21WAF1/CIP1 IN PC-3 PROSTATE
AR AND NEK2
CANCER CELLS
Tinzl M.1, Dizeyi N.1, Zhang Y.1, Ribero D.1, Bjartell A.1, Marberger M.2, Kentaro M., Tomoaki T., Hidenori K., Katsuyuki K., Tatsuya N.
Osaka City University Graduate School, Dept. of Urology, Osaka, Japan 1Lund University, Dept. of Urological Research, Malmö, Sweden, 2University of Vienna, Dept. of Urology, Vienna, Austria Introduction & Objectives: Dietary genistein, a phytoestrogen derived
Introduction & Objectives: Estrogen signalling in advanced prostate cancer is still
from soybean, has been suggested as a chemo preventive agent for XQFOHDU(VWUDGLRO(DQGPHWDEROLWHVRI'+7FDQVHOHFWLYHO\DFWLYDWH(5˟DQ prostate cancer. Genistein has been reported to exert its anticancer estrogen receptor which proposed functions also include antiproliferative action. The HᚎHFWV YLD D YDULHW\ RI IXQFWLRQDO SDWKZD\V EXW WKH XSVWUHDP VLJQDOOLQJ DLPRIWKLV[HQRJUDIWPRGHOZDVWRHOXFLGDWHWKHIXQFWLRQRI(5˟LQDFKHPRWKHUDS\ of molecules regulated by genistein remains unclear. In this study, we UHJLPHQZLWKGRFHWD[HODQG(VWUDGLRO(KLJKDQGORZGRVHದRQRᚎVFKHGXOHDQG LQYHVWLJDWHGZKHWKHU(5˟ZDVLQYROYHGLQJHQLVWHLQLQGXFHGH[SUHVVLRQRI '+7DQGLWVHᚎHFWRQWXPRXUJURZWKH[SUHVVLRQRIVWHURLGUHFHSWRUVDQGDPLWRWLF FHOOF\FOHLQKLELWRUVLQ3&SURVWDWHFDQFHUFHOOV Material & Methods: &HOOSUROLIHUDWLRQRI3&H[SRVHGWRJHQLVWHLQZDV
Material & Methods: Tumours were induced in 6 weeks old NMRI nude mice by
injection of LnCaP cells ( 2x10 6PLOOLRQFHOOVLQERWKᚐDQNVRIWKHDQLPDOV0LFH
measured by WST-1 proliferation assay. The expression of p21, p27 bearing tumours of > 200 mm were castrated, randomized in 5 groups and treatment DQG (5˟ LQ 3& FHOOV ZDV DVVHVVHG E\ TXDQWLWDWLYH UHDOWLPH UHYHUVH ZLWK'RFHWD[HOLSPJNJ'RFHWD[HODQG(VWUDGLROLQRQRᚎVFKHGXOH+LJK WUDQVFULSWLRQ3&5(5˟VLOHQFLQJZDVSHUIRUPHGXVLQJDVPDOOLQWHUIHULQJ GRVHPJNJRUORZGRVHPJNJVFRQHZHHNRQRQHZHHNRᚎRU'RFHWD[HO RNA (siRNA). The transcriotional activity of p21 promoter was determined and DHT ( 1mg/kg – on schedule weekly ) started when tumours were considered DVDQGURJHQLQGHSHQGHQW0LFHZHUHVDFULᚏFHGZKHQWKH\ZHUHFRPSURPLVHGE\excessive tumour load. Tumours were harvestd and immunohistochemical staining Results: Genistein caused marked inhibition of proliferative activity and
IRU(5˟$536$.LDQG1HNSHUIRUPHG LQGXFHGWKHH[SUHVVLRQRISDQG(5˟LQ3&FHOOV7KHVL51$DJDLQVW(5˟VXSSUHVVHGWKHJHQLVWHLQLQGXFHGH[SUHVVLRQRISDQGUHGXFHGWKH Results: Tumour growth was 2 fold increased in the high- dose E2 and low -dose
E2 treated group compared to the control group. Interestingly, combination therapy
transactivation activity of p21 promoter induced by genistein.
RI'+7DQGGRFHWD[HOFDXVHGDVLJQLᚏFDQWUHGXFWLRQRIWXPRXUYROXPHand tumours < 250 mm disappeared. Tumour size in docetaxel treated mice could Conclusions: (5˟ ZDV LQYROYHG LQ JHQLVWHLQLQGXFHG H[SUHVVLRQ RI S
only be stabilized over 2 cycles. Immunohistochemical staining showed a correlation RI(5˟H[SUHVVLRQH[SUHVVLRQRI1HNDQG$5LQKLJKGRVH(WUHDWHGPLFHDQGDHT treated mice.
Conclusions: Combination of docetaxel and intermittent DHT application reduced
WXPRXUYROXPHVLJQLᚏFDQWO\LQWKLVDQLPDOPRGHO'+7PLJKWSURPRWHFKHPRVHQVLWLYLW\
WRGRFHWD[HOE\FRPSOH[PRGXODWLRQRI(5˟$5DQGPLWRWLFNLQDVHVOLNH1HN
BENEFICIAL EFFECTS ON LNCAP PROSTATE CANCER CELLS
AN EXPERIMENTAL STUDY IN NUDE MICE ON THE
DERIVED FROM HISTONE DEACETYLASE INHIBITOR TREATMENTS
ELECTROMAGNETIC DIAGNOSIS OF TUMOURS
Strauss A.1, Schweyer S.2, Ringert R.H.1, Thelen P.1 Tubaro A.1, De Nunzio C.1, Stoppacciaro A.2, Leonetti C., Zupi G., Miano L.1 1Ospedale Sant’Andrea, “La Sapienza University”, Dept. of Urology, Rome, Italy, 2Ospedale Sant’Andrea, 1Georg-August-University, Dept. of Urology, Göttingen, Germany, 2Georg- “La Sapienza University”, Dept. of Pathology, Rome, Italy, National Cancer Institute “Regina Elena”, August-University, Dept. of Pathology, Göttingen, Germany Laboratory for Preclinical Experimental Chemotherapy, Rome, Italy Introduction & Objectives: Tissue resonance interference is a new technique for the electromagnetic
Introduction & Objectives: 7KH EHQHᚏW RI KLVWRQH GHDFHW\ODVH LQKLELWRUV
diagnosis of human neoplasm. Preliminary data were published on the diagnostic accuracy of the (HDACi) in oncology is currently under intense investigation and already has been TRIMprob in the prostate and breast tumours. No experimental data on any animal model are available. )ROORZLQJWRDSUHOLPLQDU\IHDVLELOLW\VWXG\FRQGXFWHGLQ-XQHDLPRXUUHVHDUFKZDVWRFRQᚏUPWKH subjected to several clinical trials. We recently introduced the HDACi valproic diagnostic capacity of the TRIMprob in the mouse model of prostate and breast cancer. Primary objective acid as an useful drug in prostate cancer treatment. Our ongoing research ZDVWRPHDVXUHVLJQDOLQWHQVLW\DWDQG0+]LQFRQWURODQLPDOVDQGLQPLFHLPSODQWHGZLWK IRFXVHVRQWKHLGHQWLᚏFDWLRQRI+'$&LHOLJLEOHIRUIXWXUHFOLQLFDOXVH7KHDLPRI EUHDVWDQGSURVWDWHFDQFHUDWGLᚎHUHQWVWDJHVRIGHYHORSPHQW WKLVVWXG\ZDVWRSUHVHQWWKHHᚎHFWVRIFDUEDPD]HSLQH&%=RQWKHH[SUHVVLRQ Material & Methods: Thirty nude mouse (15 males and 15 females) (Charles River, Wilmington, MA,
of genes relevant in tumour cell proliferation, apoptosis and invasion.
86$ ZHUH VWDELOLVHG LQ RXU DQLPDO IDFLOLW\ IRU D ZHHN 0LFH ZHUH WKHQ PDUNHG IRU IXUWKHU LGHQWLᚏFDWLRQDQGH[DPLQHGZLWKWKH75,0SURE$OOPHDVXUHVZHUHSHUIRUPHGLQWULSOLFDWH(YHU\ZHHNIRUZHHNVDgroup of 5 male mice were then injected with 105 Material & Methods: Expression analyses in CBZ-treated LNCaP prostate
FHOOVRI3&DQGIHPDOHPLFH&*FHOOOLQHVVXVSHQGHG in HBSS (50 microL) in both the left tight (intramuscular) and in the right shoulder (subcutaneous). Four cancer cells were performed by real time RT-PCR (Bio-Rad iCycler and weeks later all animals were anaesthetised and were examined again with the TRIMprob. Tumour size software). Tumour cell viability and proliferation were assessed by AlamarBlue- was measured in all animals using a calliper. At week 5, subcutaneous tumours were excised and HOHFWURPDJQHWLF WHVW SHUIRUPHG DJDLQ $OO DQLPDOV ZHUH WKHQ VDFULᚏFHG DOO WXPRXUV ZHUH H[FLVHG ᚏ[HGand processed for histology.
Results: Treatments with CBZ depending on concentration induced the
Results: Comparison of TRIMprob data in mice with prostate cancer and breast neoplasm showed no
expression of several genes which has been silenced in LNCaP prostate cancer GLᚎHUHQFHEHWZHHQWKHWZRWXPRXUVVRGDWDRIWKHWZRQHRSODVPVZHUHSRROHGWRJHWKHU&RPSDULVRQRISDLUHGGDWDREWDLQHGLQHDFKPRXVHEHIRUHDQGDIWHULQWUDPXVFXODUWXPRXULPSODQWVKRZHGDVLJQLᚏFDQW FHOOVP51$H[SUHVVLRQRIHVWURJHQUHFHSWRU˟DQG,*)%3ZHUHXSUHJXODWHG UHGXFWLRQRIVLJQDOLQWHQVLW\ZDVPHDVXUHGDWLQFUHDVHRIVLJQDOLQWHQVLW\ZDVREVHUYHGDWDQG Concomitantly, down-regulated expression was observed for the androgen UHFHSWRU FRDFWLYDWRU 3'() IRU 36$ DQG '' ,Q DGGLWLRQ &%= GHFUHDVHG viability and proliferation of LNCaP cells.
Conclusions: +'$&L &%= DW PRGHUDWH FRQFHQWUDWLRQV DᚎHFWV WKH H[SUHVVLRQ
of highly relevant factors, rectifying their aberrant expression status in prostate Similar results were obtained in the analysis of subcutaneously implanted tumours. In the prostate cancer FDQFHU 7KH HVWURJHQ UHFHSWRU˟ D SXWDWLYH WXPRXU VXSUHVVRU DQG ,*)%3 PRGHO VLJQLᚏFDQW FRUUHODWLRQ ZDV IRXQG EHWZHHQ VL]H RI WKH WXPRXU LPSODQWHG LP DQG ERWK WKH VLJQDO an inhibitory factor of the IGF-axis are increased in expression. In contrast, LQWHQVLW\DW0+]FRUUHODWLRQFRHᚑFLHQWSDQGVLJQDOUHGXFWLRQIURPEDVHOLQHWRZHHNV the expression of PDEF is down-regulated after treatment with CBZ which S$QDO\VLVRI75,0SUREVLJQDOLQFRQWUROPLFHVKRZHGQRFKDQJHRYHUWKHVWXG\SHULRGdue to aging FRQVHTXHQWO\DᚎHFWVPDUNHUVRISURVWDWHFDQFHU36$DQGPRVWSUREDEO\''7KHVH EHQHᚏFLDO HᚎHFWV RI &%= ZLGHQ WKH VFRSH IRU +'$&LWUHDWPHQWV RI Conclusions: 7KHVH GDWD SURYLGH WKH ᚏUVW H[SHULPHQWDO HYLGHQFH WKDW HOHFWURPDJQHWLF GLDJQRVLV RI
prostate cancer adding another established drug with known and manageable cancerous tissue by tissue reference interaction with TRIMprob is feasible in the mouse model. Our GDWD FRQᚏUP GDWD SUHYLRXVO\ SXEOLVKHG E\ RXU JURXS DQG RWKHU LQ WKH SHHU UHYLHZ OLWHUDWXUH IRVWHU QHZFROODERUDWLYHUHVHDUFKHᚎRUWLQWKLVDUHDDQGRSHQDQHZSHUVSHFWLYHLQFDQFHUGLDJQRVLV

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