Szlak liganda czynnika martwicy nowotworu indukującego apoptozę (TRAIL) jako potencjalny cel terapii w raku prostaty

Pełen tekst

(1)35$&$32*/Ą'2:$. Szlak liganda czynnika martwicy nowotworu indukującego apoptozę (TRAIL) jako potencjalny cel terapii w raku prostaty 7KHSDWKZD\RIWXPRUQHFURVLVIDFWRUUHODWHGDSRSWRVLV LQGXFLQJOLJDQG 75$,/

(2) DVDSRWHQWLDOWDUJHWLQWKHUDS\ RISURVWDWHFDQFHU Magdalena Kowalska, Ewelina Szliszka, Wojciech Król. ST R ES Z CZ E NI E 5DN SURVWDW\ MHVW MHGQ\P ] QDMF]ĊĞFLHM Z\VWĊSXMąF\FK QRZRWZRUyZ ]áRĞOLZ\FK XPĊĪF]\]Q/LJDQGF]\QQLNDPDUWZLF\QRZRWZRUXLQGXNXMąF\DSRSWR]Ċ tumor necrosis factor-related apoptosis-inducing ligand±75$,/ $SR/

(3) MHVW F\WR NLQą QDOHĪąFą GR QDGURG]LQ\ F]\QQLND PDUWZLF\ QRZRWZRUX tumor necrosis factor ± 71)

(4) 75$,/ PD ]GROQRĞü LQGXNRZDQLD DSRSWR]\ Z NRPyUNDFK UDND SURVWDW\QLHEĊGąFWRNV\F]Q\PZVWRVXQNXGRSUDZLGáRZ\FKNRPyUHNFRF]\QL JR MHGQ\P ]SRWHQFMDOQ\FK OHNyZ SU]HFLZQRZRWZRURZ\FK 3RSU]H] LQWHUDNFMĊ ]UHFHSWRUDPL75$,/5'5L75$,/5'5 QD SRZLHU]FKQLNRPyUHNUDND SURVWDW\ XUXFKDPLD WUDQVGXNFMĊ V\JQDáX GR DSRSWR]\ 5HNRPELQRZDQ\ 75$,/ LSU]HFLZFLDáD VZRLVWH Z VWRVXQNX GR UHFHSWRUyZ 75$,/5 L 75$,/5 Z\ ND]XMą VDW\VIDNFMRQXMąFH HIHNW\ WHUDSHXW\F]QH Z EDGDQLDFK NOLQLF]Q\FK , L ,, ID]\ 1LHVWHW\ ZLHOH NRPyUHN QRZRWZRURZ\FK Z W\P NRPyUHN UDND SURVWDW\ Z\ND]XMHRSRUQRĞüQDDSRSWR]ĊPHGLRZDQąSU]H]75$,/0HFKDQL]P\75$,/ RSRUQRĞFLNRPyUHNUDNDSURVWDW\GRW\F]ąZLHOXHWDSyZV]ODNXDSRSWR]\=LGHQ W\ILNRZDQR V]HUHJ F]\QQLNyZ FKHPLF]Q\FK F\WRVWDW\NL

(5) RUD] IL]\F]Q\FK SUR PLHQLRZDQLH JDPPD

(6) NWyUH PRJą XZUDĪOLZLDü NRPyUNL UDND SURVWDW\ L SU]HáD PDüLFKRSRUQRĞüQDG]LDáDQLH75$,/. Katedra i Zakład Mikrobiologii i Immunologii Wydziału Lekarskiego z Oddziałem Lekarsko-Dentystycznym w Zabrzu Śląskiego Uniwersytetu Medycznego w Katowicach. 6à2:$ ./8& =2:( . ADRES DO KORESPONDENCJI:. 75$,/ UHFHSWRU\ 75$,/ DSRSWR]D UDN SURVWDW\ PHFKDQL]P\ 75$,/ RSRUQRĞFLSU]HáDP\ZDQLHRSRUQRĞFLQD75$,/ FKHPLRWHUDSLDUDGLRWHUDSLD

(7) . Prof. dr hab. n. med. Wojciech Król Katedra i Zakład Mikrobiologii i Immunologii Wydziału Lekarskiego z Oddziałem Lekarsko-Dentystycznym w Zabrzu Śląskiego Uniwersytetu Medycznego w Katowicach ul. Jordana 19 41-808 Zabrze tel. +48 32 272 25 54 e-mail: wkrol@sum.edu.pl. A B ST R A CT 3URVWDWH FDQFHU LV RQH RI WKH PRVW FRPPRQ PDOLJQDQW WXPRUV LQ PHQ 7XPRU QHFURVLVIDFWRUUHODWHGDSRSWRVLVLQGXFLQJOLJDQG 75$,/$SR/

(8) LVDF\WRNLQH RIWKHWXPRUQHFURVLVIDFWRU 71)

(9) VXSHUIDPLO\75$,/SRVVHVVHVWKHDELOLW\WR LQGXFHDSRSWRVLVLQSURVWDWHFDQFHUFHOOVZLWKRXWWR[LFLW\WRQRUPDOFHOOVZKLFK PDNHVLWRQHRIWKHSRWHQWLDODQWLFDQFHUGUXJV75$,/DFWLYDWHVWKHWUDQVGXFWLRQ. Ann. Acad. Med. Siles. 2013, 67, 5, 315–321 Copyright © Śląski Uniwersytet Medyczny w Katowicach eISSN 1734-025X. . 315.

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

(11) DV ZHOO DV SK\VLFDO JDPPD UDGLDWLRQ

(12) KDYH EHHQ LGHQWLILHG WR VHQVLWL]H SURVWDWH FDQFHUFHOOVDQGRYHUFRPHWKHLUUHVLVWDQFHWR75$,/ .(<:25'6. 75$,/ 75$,/ UHFHSWRUV DSRSWRVLV SURVWDWH FDQFHU PHFKDQLVPV RI 75$,/UHVLVWDQFH RYHUFRPH 75$,/ UHVLVWDQFH FKHPRWKHUDS\UDGLRWKHUDS\

(13) 75$,/ WR ELDáND EáRQRZH W\SX , ]DZLHUDMąFH ]H ZQąWU]NRPyUNRZą ERJDWą Z F\VWHLQĊ 1NRĔFRZą -HGQą] RELHFXMąF\FKWHUDSLLZOHF]HQLXUDND SURVWDW\ GRPHQĊUR]SR]QDMąFąOLJDQG75$,/5L75$,/5 PRĪH E\ü ]DVWRVRZDQLH OLJDQGD F]\QQLND PDUWZLF\ QD]\ZDQHUHFHSWRUDPLĞPLHUFL death receptor±'5

(14) QRZRWZRUX LQGXNXMąFHJR DSRSWR]Ċ tumor necrosis SRVLDGDMą ZHZQąWU]NRPyUNRZą GRPHQĊ ĞPLHUFL factor-related apoptosis-inducing ligand 75$,/ death domain ± ''

(15) QLH]EĊGQą GR DNW\ZDFML ]H $SR/

(16) =RVWDáRQRGNU\W\ZODWDFK±MDNR ZQąWU]SRFKRGQHJR V]ODNX DSRSWR]\ >@ 1DWR NROHMQD F]ąVWHF]ND QDOHĪąFD GR URG]LQ\ 71) tumor PLDVW SU]\áąF]HQLH OLJDQGD 75$,/ GR 75$,/5 OXE necrosis factor

(17) SU]H]GZDQLH]DOHĪQH]HVSRá\EDGDZ 75$,/5 QLH LQLFMXMH SURFHVX DSRSWR]\ SRQLHZDĪ F]H >@ -DN ZLĊNV]RĞü F]áRQNyZ URG]LQ\ 71) UHFHSWRU\ WH FKDUDNWHU\]XMH F]ĊĞFLRZ\ OXE FDáNRZLW\ 75$,/ MHVW ELDáNLHP EáRQRZ\P W\SX ,, ]áRĪRQ\P EUDNZHZQąWU]NRPyUNRZHMGRPHQ\ĞPLHUFL5HFHSWR ]DPLQRNZDVyZ-HJRF]ąVWHF]ND]EXGRZDQDMHVW U\ WH RNUHĞODQH MDNR ÄSXáDSNL´ OXE ÄZDELNL´ decoy ] GZyFK ]DVDGQLF]\FK IUDJPHQWyZ &WHUPLQDOQHM receptor ± 'F

(18) SU]H] NRQNXURZDQLH ] UHFHSWRUDPL GáXJLHM DPLQRNZDVRZHM

(19) GRPHQ\ SR]DNRPyU ĞPLHUFL R SU]\áąF]HQLH 75$,/ PRJą KDPRZDü DSRS NRZHM RUD] 1WHUPLQDOQHM L NUyWNLHM DPLQR WR]Ċ SURPXMąF SUROLIHUDFMĊ RUD] SU]HĪ\FLH NRPyUHN NZDVRZHM

(20) GRPHQ\ F\WRSOD]PDW\F]QHM 'RPHQD QRZRWZRURZ\FK >@ 3RGREQLH 23* QLH SRVLDGD &NRĔFRZD 75$,/ Z\ND]XMH GXĪą KRPRORJLĊ ] SR IXQNFMRQDOQHMGRPHQ\ĞPLHUFL6WZLHUG]RQRĪHMHGHQ GREQ\PL GRPHQDPL LQQ\FK SU]HGVWDZLFLHOL ] URG]LQ\ ] UHFHSWRUyZ 75$,/5 OXE 75$,/5 PRĪH E\ü 71) WDNLFK MDN OLJDQG )DV )DV/

(21) L 71)Į >@ GRPLQXMąF\ Z WUDQVGXNFMLV\JQDáXGRĞPLHUFLNRPyU *HQ\ NRGXMąFH ELDáNR 75$,/ ]ORNDOL]RZDQH Vą QD NL 75$,/5 RGJU\ZD ]DVDGQLF]ą UROĊ Z LQGXNFML GáXJLPUDPLHQLXFKURPRVRPXZSR]\FMLT>@ DSRSWR]\ Z NRPyUNDFK ELDáDF]HN QDWRPLDVW Z\VRND &]ąVWHF]ND 75$,/ Z\VWĊSXMH Z SRVWDFL UR]SXV]F]DO HNVSUHVMD L DNW\ZDFMD 75$,/5 PD NOXF]RZH ]QD QHM soluble 75$,/ ± V75$,/

(22) OXE MHVW ]ZLą]DQD F]HQLH GOD 75$,/PHGLRZDQHM DSRSWR]\ NRPyUHN ]SRZLHU]FKQLą NRPyUHN LPPXQRNRPSHWHQWQ\FK OLW\FK JX]yZ QRZRWZRURZ\FK 5HFHSWRU\ ĞPLHUFL Vą WDNLFK MDN OLPIRF\W\ 7 L NRPyUNL 1. PDNURIDJL REHFQLH SRVWU]HJDQH MDNR DWUDNF\MQ\ FHO Z WHUDSLL QHXWURILOLH F]\ NRPyUNL GHQGU\W\F]QH >@ 2ELH SU]HFLZQRZRWZRURZHM>@ IRUP\ IXQNFMRQXMą MDNR WULPHU\ L Z\ZRáXMą DSRSWR]Ċ SRSU]H] RGG]LDá\ZDQLH ]H VZRLVW\PL UHFHSWRUDPL Rola liganda TRAIL w procesie apoptozy Z\VWĊSXMąF\PL QD SRZLHU]FKQL NRPyUHN GRFHORZ\FK >@ /LJDQG 75$,/ LQGXNXMH DSRSWR]Ċ Z NRPyUNDFK /LJDQG75$,/RUD]MHJRUHFHSWRU\ĞPLHUFLRGJU\ZDMą QRZRWZRURZ\FK QLHEĊGąFWRNV\F]Q\ Z VWRVXQNXGR ZDĪQą UROĊ Z LQGXNRZDQLX DSRSWR]\ Z NRPyUFH QR SUDZLGáRZ\FKNRPyUHNRUJDQL]PX>@)L]MRORJLF]QH ZRWZRURZHM >@ 75$,/5 L 75$,/5 ]D ]QDF]HQLH75$,/QLH]RVWDáRZSHáQLSR]QDQH=DRE SRPRFą GRPHQ\ ]HZQąWU]NRPyUNRZHM ZLąĪą OLJDQG VHUZRZDQR ĪH HQGRJHQQ\ 75$,/ RGJU\ZD LVWRWQą QDWRPLDVW G]LĊNL ZHZQąWU]NRPyUNRZHM GRPHQLH UROĊZQDG]RU]HLPPXQRORJLF]Q\PRUD]ZQLV]F]HQLX ĞPLHUFL ''

(23) SU]\áąF]DMą ELDáNR DGDSWRURZH )$'' QLHSUDZLGáRZ\FK QRZRWZRURZ\FK NRPyUHN > fasassociated death domain

(24) >@ : WHQ VSRVyE @ SRZVWDMH NRPSOHNV V\JQDáRZ\ ',6& death initiated :\UyĪQLDP\ SLĊü URG]DMyZ UHFHSWRUyZ GOD OLJDQGD signaling complex

(25) ]DSRF]ąWNRZXMąF\ SURFHV DSRSWR 75$,/ 75$,/5 '5

(26) 75$,/5 '5

(27) ]\ >@ 1DVWĊSQLH SU]H] Z\NRQDZF]ą GRPHQĊ 75$,/5 'F5

(28) 75$,/5 'F5

(29) L RVWHRSURWH ĞPLHUFL ±'(' death execution domain

(30) VWDQRZLąFą JHU\QĊ 23*

(31) >@ *HQ\ GOD W\FK UHFHSWRUyZ 1NRĔFRZąF]ĊĞüELDáNDDGDSWRURZHJRGRNRPSOHNVX ]QDMGXMą VLĊ QD NUyWNLP UDPLHQLX FKURPRVRPX ',6& ]RVWDMH SU]\áąF]RQD SURNDVSD]D $NW\ZDFMD S

(32) >@ 3R]D 23* NWyUD MHVW UHFHSWRUHP UR] NRPSOHNVX ',6& SURZDG]L GR XZROQLHQLD HQ]\PX SXV]F]DOQ\P ZV]\VWNLH SR]RVWDáH UHFHSWRU\ GOD SURWHROLW\F]QHJR ± NDVSD]\ $NW\ZQD NDVSD]D Ligand TRAIL i jego receptory. 316.

(33) SZLAK TRAIL JAKO CEL TERAPII W RAKU PROSTATY. ]DSRF]ąWNRZXMH DXWRNDWDOLW\F]Qą NDVNDGĊ NDVSD] HIHNWRURZ\FKL>@,ORĞüSRZVWDáHJRNRP SOHNVX ',6& DNW\ZRZDQHJR SRSU]H] V]ODN ]HZQąWU] SRFKRGQ\ UHFHSWRURZ\

(34) MHVW Z\VWDUF]DMąFD GR XUX FKRPLHQLD SURFHVX DSRSWR]\ Z NRPyUNDFK RNUHĞOD Q\FKMDNRNRPyUNLW\SX, : RGUyĪQLHQLX RG QLFK VW\PXODFMD NRPyUHN W\SX ,, Z\PDJD GRGDWNRZR SU]HND]\ZDQLD V\JQDáX ] PLWR FKRQGULXP ]H V]ODNX ZHZQąWU]SRFKRGQHJR

(35) >@ :VSyOQ\P HOHPHQWHP GOD ]HZQąWU]SR FKRGQHJR UHFHSWRURZHJR

(36) L ZHZQąWU]SRFKRGQHJR PLWRFKRQGULDOQHJR

(37) V]ODNXMHVWNDVSD]D$NW\ZDFMD V]ODNX ]DOHĪQHJR RG PLWRFKRQGULyZ ]ZLą]DQD MHVW ]H ]GROQRĞFLą NDVSD]\ GR UR]V]F]HSLHQLD ELDáND %LG BH3-interacting domain death agonist

(38) QDOHĪąFHJR GR URG]LQ\ %FO B-cell leukemia/lymphoma-2

(39) >@ %LG XOHJD SURWHROLW\F]QHM PRG\ILNDFML GR IRUP\W%LG truncated Bid

(40) NWyUDSU]HPLHV]F]DVLĊGR ]HZQĊWU]QHM EáRQ\ PLWRFKRQGULDOQHM L ZUD] ] LQQ\PL SURDSRSWRW\F]Q\PL ELDáNDPL ] URG]LQ\ %FO %D[ %DG RUD] %DN

(41) XF]HVWQLF]\ Z WZRU]HQLX NDQDáyZ PL WRFKRQGULDOQ\FKRGSRZLDGDMąF\FK]DVSDGHNSRWHQFMD áX PLWRFKRQGULDOQHJR RUD] XZROQLHQLH F\WRFKURPX c L6PDF'LDEOR second mitochondrial activator of caspases/direct inhibitor of apoptosis binding protein. with low isoelectric point

(42) >@&\WRFKURPcSU]H FKRG]L GR F\WRSOD]P\ WZRU]ąF ZUD] ] SURNDVSD]ą $73 adenosine-5'-triphosphate

(43) RUD]ELDáNLHP$SDI apoptotic protease activating factor-1

(44) NRPSOHNV QD]\ZDQ\DSWRVRPHP:REUĊELHDSRSWRVRPXGRFKR G]L GR SU]HNV]WDáFHQLD SURNDVSD]\ GR NDVSD]\ NWyUDQDVWĊSQLHDNW\ZXMHNDVSD]\HIHNWRURZHJáyZQLH NDVSD]Ċ >@ $NW\ZDFMD GURJL ZHZQąWU]SR FKRGQHM PLWRFKRQGULDOQHM

(45) Z]PDFQLD WUDQVGXNFMĊ V\JQDáX GR DSRSWR]\ ]H V]ODNX UHFHSWRURZHJR ]H ZQąWU]SRFKRGQHJR

(46) *áyZQH V]ODNL 75$,/PHGLR ZDQHM DSRSWR]\ RUD] PHFKDQL]P\ 75$,/RSRUQRĞFL ZNRPyUNDFKUDNDSURVWDW\SU]HGVWDZLDU\FLQD Rak prostaty 5DN SURVWDW\ MHVW MHGQ\P ] QDMF]ĊĞFLHM GLDJQR]RZD Q\FKQRZRWZRUyZ]áRĞOLZ\FKVWDQRZLąFGUXJąFRGR F]ĊVWRĞFL SU]\F]\QĊ ]JRQyZ ZĞUyG PĊĪF]\]Q Z 8QLL (XURSHMVNLHM L Z 6WDQDFK =MHGQRF]RQ\FK >@ 'R F]\QQLNyZ U\]\ND ]DFKRURZDQLD QDOHĪą ZLHN GLHWD SUHG\VSR]\FMHG]LHG]LF]QHRUD]SRFKRG]HQLHHWQLF]QH >@ : RVWDWQLFK NLONXG]LHVLĊFLX ODWDFK REVHUZXMH P\ ]QDF]Q\ Z]URVW ]DSDGDOQRĞFL QD UDND SURVWDW\ FRPRĪHZLą]DüVLĊ]Z\GáXĪHQLHPĪ\FLDSDFMHQWyZ. Ryc. 1. Szlaki TRAIL-indukowanej apoptozy oraz mechanizmy TRAIL-oporności w komórkach raka prostaty. Fig. 1. Pathways of TRAIL-induced apoptosis and mechanisms of TRAIL-resistance in prostate cancer cells.. . 317.

(47) ANNALES ACADEMIAE MEDICAE SILESIENSIS 2013, 67, 5. D WDNĪH ] UR]ZRMHP QRZ\FK PHWRG GLDJQRVW\F]Q\FK ZSURZDG]DQ\FK GR FRG]LHQQHM SUDNW\NL NOLQLF]QHM WDNLFKMDN R]QDF]HQLH36$ prostate specific antigen VZRLVW\ DQW\JHQ VWHUF]RZ\

(48) Z VXURZLF\ NUZL > @ 0ROHNXODUQH PHFKDQL]P\ RGSRZLHG]LDOQH ]D LQLFMR ZDQLHLUR]ZyMUDNDSURVWDW\QLH]RVWDá\ZSHáQLZ\MD ĞQLRQH >@ -HVW WR QRZRWZyU KRUPRQR]DOHĪQ\ :H ZF]HVQ\PVWDGLXP RJUDQLF]RQ\PGRQDU]ąGX

(49) FKRU]\ NZDOLILNRZDQL Vą GR SURVWDWHNWRPLL UDG\NDOQHM OXE UDGLRWHUDSLL : SU]\SDGNX ]DDZDQVRZDQHM FKRURE\ OHF]HQLHP ] Z\ERUX MHVW KRUPRQRWHUDSLD F]ĊVWR ZVNRMDU]HQLX ] UDGLR OXE FKHPLRWHUDSLą >@ 3RPL PR VWRVRZDQLD W\FK PHWRG GRFKRG]L GR ]DEXU]HĔ ZLQGXNFMLDSRSWR]\NRPyUHNUDNDF]HJRNRQVHNZHQ FMąMHVWQLHSRZRG]HQLHZ\PLHQLRQ\FKZF]HĞQLHMWHUD SLL SU]HFLZQRZRWZRURZ\FK = F]DVHP UDN SURVWDW\ VWDMH VLĊ RSRUQ\ QD KRUPRQRWHUDSLĊ &53& ± castration resistant prostate cancer

(50) =D MHGQą ] SU]\F]\Q SRZVWDQLD &53& XZDĪD VLĊ GHUHJXODFMH SURFHVyZ DSRSWR]\ GODWHJR WHĪ REHFQLH GR JáyZQ\FK FHOyZ VWUDWHJLL OHF]HQLD &53& QDOHĪ\ XUXFKRPLHQLH Z NR PyUNDFK QRZRWZRURZ\FK PHFKDQL]PyZ SURZDG]ą F\FKGRDSRSWR]\>@ Mechanizmy oporności na TRAIL :LHOH NRPyUHN QRZRWZRURZ\FK Z W\P NRPyUHN UDNDSURVWDW\Z\ND]XMHRSRUQRĞüQDDSRSWR]ĊPHGLR ZDQą SU]H] 75$,/ 0HFKDQL]P\ 75$,/RSRUQRĞFL NRPyUHN UDND SURVWDW\ QLH ]RVWDá\ MHV]F]H Z SHáQL SR]QDQH >@ 8ZDĪD VLĊ ĪH RSRUQRĞü WD PRĪH GRW\F]\ü ZLHOXHWDSyZV]ODNX DSRSWR]\>@:UDĪOL ZRĞü NRPyUHN QRZRWZRURZ\FK QD 75$,/ Z\QLND PLQ ] UyĪQLF Z HNVSUHVML UHFHSWRUyZ ĞPLHUFL QD LFK SRZLHU]FKQL 2EQLĪRQDHNVSUHVMDUHFHSWRUyZ75$,/ 5L75$,/5RUD]PXWDFMHJHQyZGODW\FKUHFHS WRUyZZNRPyUNDFKUDNDSURVWDW\PRJąSURZDG]LüGR 75$,/RSRUQRĞFL>@=NROHL]ZLĊNV]RQDHNVSUHVMD ÄUHFHSWRUyZZDELNyZ´V]F]HJyOQLH75$,/5FKUR QL NRPyUNL UDND SURVWDW\ SU]HG DSRSWR]ą LQGXNRZDQą SU]H]75$,/>@ :\ND]DQR ĪH ZUDĪOLZRĞü NRPyUHN UDND SURVWDW\ QD 75$,/ ]DOHĪ\ RG REHFQRĞFL ZHZQąWU]NRPyUNRZ\FK ELDáHN LQKLELWRUyZ WUDQVGXNFML V\JQDáX SURZDG]ąFHJR GR DSRSWR]\ >@ 3U]\NáDGHP MHVW ]ZLĊNV]RQD HNVSUHVMD ELDáND )/,3 )/,&( ± FAAD-like inerleukin-1beta-converting enzyme – inhibitory protein

(51) NWyUHáąF]\VLĊ]NRPSOHNVHP',6&XQLHPRĪOLZLDMąF DNW\ZDFMĊSURNDVSD]\>@ .ROHMQ\P ZDĪQ\P HOHPHQWHP ]ZLą]DQ\P ] RSRUQR ĞFLą NRPyUHN UDND SURVWDW\ QD G]LDáDQLH OLJDQGX 75$,/ MHVW QDVLORQD HNVSUHVMD LQKLELWRUyZ ] URG]LQ\ ,$3V inhibitor of apoptosis proteins

(52) F,$3 F,$3 cellular inhibitor of apoptosis 1 and 2

(53) ;,$3 X-linked inhibitor of apoptosis

(54) VXUZLZLQ\>@%LDáND ,$3V]ZáDV]F]D;,$3EORNXMąDNW\ZDFMĊNDVSD]\. 318. . RUD] 1DWRPLDVW 6PDF'LDEOR RGSRZLDGD ]D KDPR ZDQLHIXQNFML,$3VZNRPyUNDFKUDNDSURVWDW\ :ZLHOXW\SDFKNRPyUHNQRZRWZRURZ\FKZ\ZRáDQLH DSRSWR]\ LQGXNRZDQHM SU]H] 75$,/ ]DOHĪ\ RG DNW\ ZDFML GURJL ZHZQąWU]SRFKRGQHM ]DOHĪQHM RG PLWR FKRQGULyZ =PQLHMV]RQDHNVSUHVMDOXEPXWDFMHELDáHN SURDSRSWRW\F]Q\FK ] URG]LQ\ %FO %D[ %DN %DG

(55) NWyUH XF]HVWQLF]ą Z XUXFKRPLHQLX PLWRFKRQGULDOQHJR V]ODNXDSRSWR]\ZNRPyUNDFKUDNDSURVWDW\Z]QDF] QHM PLHU]H SU]\F]\QLDMą VLĊ GR 75$,/RSRUQRĞFL >@1LHEH]]QDF]HQLDSR]RVWDMHWDNĪHQDGHNVSUH VMDELDáHNDQW\DSRSWRW\F]Q\FK]URG]LQ\%FO %FO %FO[/

(56) NWyUH EORNXMą SURDSRSWRW\F]QH %D[ L %DN ]DSRELHJDMąF ]ZLĊNV]HQLX SU]HSXV]F]DOQRĞFL EáRQ\ PLWRFKRQGULXP L VSDGNRZL SRWHQFMDáX PLWRFKRQGULDO QHJR >@ 2SRUQRĞü NRPyUHN UDND SURVWDW\ QD DSRSWR]Ċ75$,/]DOHĪQą ZLąĪH VLĊ UyZQLHĪ ] QLHSUD ZLGáRZ\P XZDOQLDQLHP ] PLWRFKRQGULyZ ELDáND 6PDF'LDEOR EĊGąFHJR DQWDJRQLVWą ELDáHN ,$3V =PQLHMV]RQH Z\G]LHODQLH OXE QLHGREyU 6PDF'LDEOR SU]\F]\QLD VLĊ GR Z]URVWX VWĊĪHQLD ELDáHN ,$3V ]QD Q\FKLQKLELWRUyZNDVSD]>@ 2SRUQRĞü ZLHOX OLQLL NRPyUNRZ\FK UDND SURVWDW\ QD DSRSWR]Ċ LQGXNRZDQą SU]H] 75$,/ XZDUXQNRZDQD MHVW DNW\ZDFMą F]\QQLND MąGURZHJR 1)ț% nuclear factor ț%

(57) 1)ț% LQGXNXMH HNVSUHVMH DQW\DSRSWR W\F]Q\FK ELDáHN ] URG]LQ\ %FO ,$3V L )/,3 >@ :NRPyUNDFK UDND SURVWDW\ ZDĪQą UROĊ Z 75$,/ RSRUQRĞFL RGJU\ZDMą PXWDFMH JHQX VXSUHVRURZHJR S %UDN IXQNFMRQDOQHJR ELDáND S protein 53

(58) SURZDG]LGR Z]PRĪRQHMHNVSUHVML%FO%FO[/RUD] ,$3V D WDNĪH EORNRZDQLD JHQX ELDáND $SDI 1LH SUDZLGáRZH ELDáNR S ]DEXU]D SURFHV UHG\VWU\EXFML UHFHSWRUyZĞPLHUFLJáyZQLHUHFHSWRUD75$,/5QD SRZLHU]FKQLNRPyUHNUDNDSURVWDW\>@ Zastosowanie TRAIL w badaniach klinicznych :EDGDQLDFKNOLQLF]Q\FK]QDOD]á\]DVWRVRZDQLHUyĪQH IRUP\75$,/SRGSRVWDFLąUHNRPELQRZDQHJROLJDQGX UKV75$,/

(59) RUD] SU]HFLZFLDá PRQRNORQDOQ\FK VZRL VW\FK Z VWRVXQNX GR UHFHSWRUyZ 75$,/5 ± PDSD WXPXPDE +*6(75

(60) OXE 75$,/5 ± OHNVDWXPX PDE +*6(75

(61) FRQDWXPXPDE $*0

(62) GUR]L WXPDE 35

(63) WLJDWX]XPDE 75$ &6

(64) DSRPDE +

(65) >@:SRUyZQDQLX]UR]SXV]F]DO Q\P 75$,/ RJURPQą ]DOHWą SU]HFLZFLDá PRQRNOR QDOQ\FK MHVW VSHF\ILF]QH SRZLQRZDFWZR GR UHFHSWR UyZĞPLHUFLRJUDQLF]DMąFH ZLą]DQLH VLĊ] ÄUHFHSWRUD PL ZDELNDPL´ 3RQDGWR +*6(75 L +*6(75 PDMą GáXĪV]\ RNUHV SyáWUZDQLD QLĪ UHNRPELQRZDQ\ 75$,/G]LĊNLF]HPXXáDWZLRQ\MHVWGREyURGSRZLHG QLHMGDZNL SU]HFLZFLDá >@:\QLNL,L,,ID]\EDGDĔ NOLQLF]Q\FK Z\ND]Dá\ ]DGRZDODMąFą VNXWHF]QRĞü LQLVNą WRNV\F]QRĞü SUHSDUDWyZ PDSDWXPXPDE L OHN VDWXPXPDE XSDFMHQWyZ ] ]DDZDQVRZDQ\PL QRZR WZRUDPLSáXFRNUĊĪQLF\LQHUHN>@.

(66) SZLAK TRAIL JAKO CEL TERAPII W RAKU PROSTATY. JR HIHNWX WHUDSHXW\F]QHJR Z\PLHQLRQH F\WRVWDW\NL VWRVRZDQH Vą ]DUyZQR Z PRQRWHUDSLL MDN L Z VNRMD U]HQLX]LQQ\PLOHNDPLSU]HFLZQRZRWZRURZ\PL>@ : GRĞZLDGF]HQLDFK in vitro ]DREVHUZRZDQR V\QHUJL VW\F]QH G]LDáDQLH WDNVDQyZ ] OLJDQGHP 75$,/ ZVWRVXQNX GR NRPyUHN UDND SURVWDW\ 8]\VNDQH Z\ QLNL SRWZLHUG]DMą ĪH WDNVDQ\ PRJą SU]HáDP\ZDü RSRUQRĞü NRPyUHN UDND SURVWDW\ QD G]LDáDQLH 75$,/ >@1LPPDQDSDOOLLZVSZ\ND]DOLĪHSDNOLWDNVHO Z VNRMDU]HQLX ] 75$,/ QDVLOD DSRSWRW\F]Q\ HIHNW OLJDQGX ]DUyZQR Z VWRVXQNX GR KRUPRQRZUDĪOLZ\FK NRPyUHNOLQLL/1&D3MDNLKRUPRQRRSRUQ\FKNRPy UHN '8 L 3& 3R ]DVWRVRZDQLX SDNOLWDNVHOX ZNRPELQDFML ] 75$,/ RGQRWRZDQR ]ZLĊNV]RQą DN W\ZDFMĊSURNDVSD]\LRUD]NDVSD]\SREXG]HQLH UR]V]F]HSLHQLD ELDáND %LG RUD] QDVLORQą DNXPXODFMĊ F\WRFKURPX c Z F\WR]ROX NRPyUHN Z\PLHQLRQ\FK ZF]HĞQLHM OLQLL UDND SURVWDW\ 0HFKDQL]P HOLPLQXMąF\ RSRUQRĞüNRPyUHNUDNDSURVWDW\QD75$,/ZLą]DáVLĊ UyZQLHĪ ] REQLĪHQLHP HNVSUHVML ELDáHN ,$3V JáyZQLH F,$3 ;,$3 >@ 8GRZRGQLRQR ĪH GRFHWDNVHO Przełamywanie TRAIL-oporności komórek raka LQGXNXMH SURFHV DSRSWR]\ ZNRPyUNDFK OLQLL 3& '8 L 5:3( SRSU]H] QDVLOHQLH DNW\ZQRĞFL ND prostaty na działanie TRAIL VSD]\ >@ <RR L ZVS SRWZLHUG]LOL ĪH F\WRVWDW\N &KHPLRWHUDSLDVWRVRZDQDMHVWZSU]\SDGNDFK]DDZDQ XZUDĪOLZLDáNRPyUNL]DUyZQRKRUPRQRZUDĪOLZHMOLQLL VRZDQHJR UDND SURVWDW\ ] SU]HU]XWDPL RUD] Z WUDNFLH /1&D3MDNLKRUPRQRRSRUQHMOLQLL&%QD75$,/ SURJUHVML FKRURE\ JG\ SRMDZLáD VLĊ RSRUQRĞü QD KRU PHGLRZDQą DSRSWR]Ċ 6\QHUJLVW\F]QH G]LDáDQLH OL PRQRWHUDSLĊ>@*áyZQ\PLF\WRVWDW\NDPLZ\NRU]\ JDQGX 75$,/ L GRFHWDNVHOX WáXPDF]\ VLĊ REQLĪHQLHP VW\ZDQ\PL Z FKHPLRWHUDSLL UDND SURVWDW\ Vą WDNVDQ\ HNVSUHVML DQW\DSRSWRW\F]Q\FK ELDáHN ] URG]LQ\ %FO WDNVRLG\

(67) VXEVWDQFMH SRFKRG]HQLD QDWXUDOQHJR JáyZQLH %FO[/

(68) ]ZLĊNV]RQ\P XZDOQLDQLHP F\WR RVLOQ\FK ZáDĞFLZRĞFLDFK SU]HFLZQRZRWZRURZ\FK FKURPXc ]PLWRFKRQGULyZRUD]DNW\ZDFMąSURNDVSD]\ >@3RF]ąWNRZR]ZLą]NLWHE\á\L]RORZDQH]NRU\ >@ FLVX GUREQROLVWQHJR Taxus brevifolia

(69) REHFQLH Z\ .ROHMQ\P ZDĪQ\P F\WRVWDW\NLHP VWRVRZDQ\P WZDU]DQHVąQDGURG]HSyáV\QWHW\F]QHMSRSU]H]PRG\ ZFKHPLRWHUDSLL UDND SURVWDW\ MHVW PLWRNVDQWURQ ± ILNDFMĊ QLHF\WRWRNV\F]QHJR QDWXUDOQHJR SUHNXUVRUD ± V\QWHW\F]Q\ DQW\ELRW\N DQWUDF\NOLQRZ\ R XGRZRG GHDFHW\OREDNDW\Q\ ,,, >@ 'R PHFKDQL]PyZ QLRQ\P G]LDáDQLX SU]HFLZQRZRWZRURZ\P >@ /HN SU]HFLZQRZRWZRURZHJR G]LDáDQLD WDNVDQyZ ]DOLF]D KDPXMH UHSOLNDFMĊ L V\QWH]Ċ '1$ ]DEXU]D QDSUDZĊ P\ ]DEXU]HQLH IXQNFML PLNURWXEXO WZRU]HQLH QLHSUD '1$ KDPXMH V\QWH]Ċ 51$ L ELDáHN RUD] EORNXMH ZLGáRZHJRZU]HFLRQDPLWRW\F]QHJRSRGF]DVSRG]LDáX DNW\ZQRĞü WRSRL]RPHUD]\ ,, SU]H] FR VSRZDOQLD NRPyUHN RUD] ]DWU]\PDQLH F\NOX NRPyUNRZHJR Z]URVW L LQZD]\MQRĞü NRPyUHN UDND SURVWDW\ >@ :OHF]HQLXRSRUQHJRQD NDVWUDFMĊUDND SURVWDW\ PLWR ZID]LH60L*RUD]LQGXNFMąDSRSWR]\>@ &KHPLRWHUDSLD ] ]DVWRVRZDQLHP WDNVDQyZ DNW\ZXMH NVDQWURQHPVWRVRZDQ\MHVW Z PRQRWHUDSLLOXE Z VNR ZNRPyUNDFK UDND SURVWDW\ PLWRFKRQGULDOQ\ V]ODN MDU]HQLX ] LQQ\PL OHNDPL WDNLPL MDN SUHGQL]RQ OXE DSRSWR]\ SRSU]H] KDPRZDQLH HNVSUHVML JHQyZ DQW\ GRFHWDNVHO >@ 'RĞZLDGF]HQLD in vitro SRWZLHU DSRSWRW\F]Q\FK ELDáHN ] URG]LQ\ %FO JáyZQLH G]DMąĪHPLWRNVDQWURQQDVLODDSRSWRW\F]QąDNW\ZQRĞü %FO[/

(70) RUD]]ZLĊNV]HQLHHNVSUHVMLS >@7DN 75$,/=DVWRVRZDQLHNRPELQDFML75$,/]PLWRNVDQ VDQ\ RGSRZLDGDMą ]D VSDGHN SRWHQFMDáX PLWRFKRQ WURQHPLQGXNXMHDSRSWR]ĊLSRSU]H]DNW\ZDFMĊNDVSD] GULDOQHJRQDVLOHQLHXZDOQLDQLDF\WRFKURPXcGRF\WR SU]HáDPXMH 75$,/RSRUQRĞü NRPyUHN UDND SURVWDW\ OLQLL3&75>@ SOD]P\RUD]LQGXNFMĊELDáND$SDI>@ 'R DNWXDOQLH VWRVRZDQ\FK WDNVDQyZ Z OHF]HQLX SD 2EHFQLH SURZDG]RQH Vą HNVSHU\PHQW\ ] ]DVWRVRZD FMHQWyZ ] ]DDZDQVRZDQ\P UDNLHP SURVWDW\ QDOHĪą QLHP UHNRPELQRZDQHJR 75$,/ RUD] SU]HFLZFLDá SDNOLWDNVHO GRFHWDNVHO WDNVDQ\ , JHQHUDFML

(71) RUD] ND PRQRNORQDOQ\FKVNLHURZDQ\FKSU]HFLZNRUHFHSWRURP ED]\WDNVHO WDNVDQ\ ,, JHQHUDFML

(72) >@ 3DNOLWDNVHO ĞPLHUFL 75$,/5 L75$,/5 2GQRWRZDQR QDVLOH LGRFHWDNVHO WR OHNL SLHUZV]HJR U]XWX Z &53& QDWR QLH F\WRWRNV\F]QHJR G]LDáDQLD OHNVDWXPXPDEX Z SR PLDVW NDED]\WDNVHO WR OHN GUXJLHJR U]XWX Z OHF]HQLX áąF]HQLX ] FLVSODW\Qą Z VWRVXQNX GR KRUPRQRRSRU &53& X FKRU\FK X NWyU\FK Z\VWąSLáD RSRUQRĞü QD Q\FKNRPyUHN3&L'86\QHUJLVW\F]QHG]LDáDQLH GRFHWDNVHOLSDNOLWDNVHO:FHOXX]\VNDQLDNRU]\VWQH REX F]\QQLNyZ WáXPDF]\ VLĊ DNW\ZDFMą NDVSD]\ %DGDQLD SU]HSURZDG]RQH SU]H] 6KLPDGD L ZVS SR WZLHUG]Lá\ F\WRWRNV\F]QH G]LDáDQLH +*6(75 ZVWRVXQNX GR NRPyUHN UDND SURVWDW\ 3U]HFLZFLDáR LQGXNXMHDSRSWR]ĊZNRPyUNDFKUDNDSURVWDW\]DUyZ QR KRUPRQRZUDĪOLZ\FK /1&D3 MDN L KRUPRQRRSRU Q\FK '8 L 3& : GRĞZLDGF]HQLDFK ]DREVHUZR ZDQR ĪH HIHNW\ZQRĞü G]LDáDQLD SU]HFLZFLDáD +*6 (75 ]DOHĪ\ RG HNVSUHVML QD SRZLHU]FKQL NRPyUHN QRZRWZRURZ\FK UHFHSWRUD ĞPLHUFL 75$,/5 +*6 (75 DNW\ZRZDá ]DUyZQR V]ODN UHFHSWRURZ\ MDN LPLWRFKRQGULDOQ\>@ :VWĊSQHEDGDQLDQDGDSRSWR]ąNRPyUHNUDNDSURVWDW\ ] ]DVWRVRZDQLHP SU]HFLZFLDá PRQRNORQDOQ\FK DQW\ 75$,/5 LOXE DQW\75$,/5 Z PRQRWHUDSLL OXE VNRMDU]HQLX ] F]\QQLNDPL FKHPLF]Q\PL F\WRVWDW\ND PL

(73) L IL]\F]Q\PL SURPLHQLRZDQLH JDPPD

(74) ZVND]XMą QD VNXWHF]QRĞü LFK G]LDáDQLD SU]HFLZQRZRWZRURZHJR RUD]PRĪOLZRĞü]DVWRVRZDQLDSU]HFLZFLDá+*6(75 Z NROHMQ\FK HWDSDFK EDGDĔ NOLQLF]Q\FK X FKRU\FK ]UDNLHPSURVWDW\. . 319.

(75) ANNALES ACADEMIAE MEDICAE SILESIENSIS 2013, 67, 5. SREXG]HQLHPSURWHROL]\ELDáND%LGGRW%LGZ]URVWHP HNVSUHVML %D[ RUD] ]ZLĊNV]HQLHP XZDOQLDQLD F\WR FKURPX c ] PLWRFKRQGULyZ 1DWRPLDVW ]DVWRVRZDQLH PDSDWXPXPDE Z VNRMDU]HQLX ] FLVSODW\Qą QLH SU]HáD P\ZDáR RSRUQRĞFL NRPyUHN UDND SURVWDW\ 3& L'8>@ 5DGLRWHUDSLD VWRVRZDQD MHVW ]DUyZQR ZH ZF]HVQ\P VWDGLDFK UDND SURVWDW\ QRZRWZyU RJUDQLF]RQ\ GR QDU]ąGX

(76) MDN L Z ]DDZDQVRZDQ\FK SRVWDFLDFK FKRUR E\:SU]\SDGNXSRGHMU]HQLDZ]QRZ\JX]DPRĪHE\ü UyZQLHĪ ]DOHFDQD Z VNRMDU]HQLX ] KRUPRQRWHUDSLą >@ 5DGLRWHUDSLD LQGXNXMH ZHZQąWU]SRFKRGQ\ PL WRFKRQGULDOQ\

(77) V]ODN DSRSWR]\ Z NRPyUNDFK QRZR WZRURZ\FK SRSU]H] Z\ZRáDQLH VWUHVX RNV\GDF\MQHJR LXV]NRG]HQLH'1$>@ 5DGLRWHUDSLD Z]PDFQLD F\WRWRNV\F]Q\ HIHNW 75$,/ ZVWRVXQNX GR KRUPRQRZDĪOLZ\FK NRPyUHN /1&D3 RUD]KRUPRQRRSRUQ\FKNRPyUHN3&L'8 8GR ZRGQLRQRĪHSURPLHQLRZDQLHJDPPDDNW\ZXMąPLWR FKRQGULDOQ\V]ODNDSRSWR]\ZNRPyUNDFKUDNDSURVWD W\SRSU]H]UHJXODFMĊSURLDQW\DSRSWRW\F]Q\FKELDáHN ]URG]LQ\%FO5DGLRWHUDSLDZNRPELQDFML]75$,/ LQGXNXMHHNVSUHVMĊELDáHN%D[L%DNRUD]KDPXMHHNV SUHVMĊELDáND%FO>@. 'RW\FKF]DVRZH Z\QLNL EDGDĔ QD NRPyUNDFK UDND SURVWDW\ ] ]DVWRVRZDQLHP 75$,/ Vą RELHFXMąFH L]DFKĊFDMą GR GDOV]\FK WHVWyZ ,VWRWQH Z\GDMH VLĊ RNUHĞOHQLH VWUDWHJLL SU]HáDP\ZDQLD RSRUQRĞFL RUD] XZUDĪOLZLHQLD NRPyUHN UDND SURVWDW\ QD G]LDáDQLH 75$,/ ] XG]LDáHP F\WRVWDW\NyZ L SURPLHQLRZDQLD JDPPD &KHPLR L UDGLRWHUDSLD DNW\ZXMą ZHZQąWU] SRFKRGQ\ PLWRFKRQGULDOQ\

(78) V]ODN DSRSWR]\ SRGF]DV JG\ SREXG]HQLH UHFHSWRUyZ ĞPLHUFL ]D SRPRFą 75$,/ XUXFKDPLD GURJĊ ]HZQąWU]SRFKRGQą UHFHSWRURZą

(79) =WHJR Z]JOĊGX OHF]HQLH SDFMHQWyZ ] UDNLHP SURVWDW\ PRĪQDE\X]XSHáQLDüSU]H]]DVWRVRZDQLH75$,/ $QDOL]D PHFKDQL]PyZ XZUDĪOLZLHQLD NRPyUHN UDND SURVWDW\ QD G]LDáDQLH 75$,/ SR]ZDOD QD Z\VXQLĊFLH KLSRWH]\ĪHUDGLROXEFKHPLRWHUDSLDSRSU]H] VW\PX ODFMĊ GURJL ] PLWRFKRQGULyZ PRJą DPSOLILNRZDü V\ JQDáSRFKRG]ąF\]HV]ODNXUHFHSWRURZHJRDNW\ZRZD QHJR SU]H] 75$,/ 3RQDGWR Z\NRU]\VWDQLH 75$,/ ZVNRMDU]HQLX]F\WRVWDW\NDPLOXEUDGLRWHUDSLąSR]ZR OLáRE\ QD ]ZLĊNV]HQLH DNW\ZQRĞFL SU]HFLZQRZRWZR URZHM ]UHGXNRZDQLH GDZNL VWRVRZDQ\FK WHUDSHXW\ NyZ L ]PQLHMV]HQLH LFK RJyOQRXVWURMRZHM WRNV\F]QR ĞFL SU]\ ]DFKRZDQLX SRĪąGDQHM VNXWHF]QRĞFL SU]H FLZQRZRWZRURZHM. PIŚMIENNICTWO 1. .UX\W)$75$,/DQGFDQFHUWKHUDS\&DQFHU/HWW± 2. :LOH\ 65 6FKRROH\ . 6PRODN 3- L ZVS ,GHQWLILFDWLRQ DQG FKDUDFWHUL]DWLRQRIDQHZ PHPEHURIWKH71)IDPLO\WKDWLQGXFHVDSRSWRVLV ,PPXQLW\± 3. 3LWWL 50 0DUVWHUV 6$ 5XSSHUW 6 'RQDKXH &- 0RRUH $ $VKNHQD]L$,QGXFWLRQRIDSRSWRVLVE\$SROLJDQGDQHZ PHPEHURIWKH WXPRU QHFURVLV IDFWRU F\WRNLQH IDPLO\ - %LRO &KHP ± ± 4. &KULVWLDQ 3$ 7KRUSH -$ 6FKZDU]H 65 9HOFDGH VHQVLWL]HV SURVWDWH FDQFHU FHOOV WR 75$,/ LQGXFHG DSRSWRVLV DQG VXSSUHVVHV WXPRU JURZWK LQ YLYR&DQFHU%LRO7KHU± 5. :X *6 75$,/ DV D WDUJHW LQ DQWLFDQFHU WKHUDS\ &DQFHU /HWW ± 6. +RORFK 3$ *ULIILWK 76 71)UHODWHG DSRSWRVLVLQGXFLQJ OLJDQG 75$,/

(80) DQHZSDWKWRDQWLFDQFHUWKHUDSLHV(XU-3KDUPDFRO ± 7. 0DQ]R ) 1HEELRVR $ 0LFHOL 0 L ZVS 71)UHODWHG DSRSWRVLV LQGXFLQJ OLJDQG VLJQDOOLQJ RI D VPDUW PROHFXOH ,QW - %LRFKHP &HOO %LRO ± 8. 6]OLV]ND ( &]XED =3 6ĊGHN à 3DUDG\V] $ .UyO : (QKDQFHG 75$,/PHGLDWHG DSRSWRVLV LQ SURVWDWH FDQFHU FHOOV E\ WKH ELRDFWLYH FRPSRXQGV QHREDYDLVRIODYRQH DQG SVRUDOLGLQ LVRODWHG IURP 3VRUDOHD FRU\OLIROLD3KDUPDFRO5HS± 9. 6]OLV]ND(.URO:6R\LVRIODYRQHVDXJPHQWWKHHIIHFWRI75$,/PHGLDWHG DSRSWRWLFGHDWKLQSURVWDWHFDQFHUFHOOV2QFRO5HS± 10. $VKNHQD]L$3DL5&)RQJ6LZVS6DIHW\DQGDQWLWXPRUDFWLYLW\RI UHFRPELQDQWVROXEOH$SROLJDQG-&OLQ,QYHVW± 11. <DJLWD + 7DNHGD . +D\DNDZD < 6P\WK 0- 2NXPXUD . 75$,/ DQGLWVUHFHSWRUVDVWDUJHWVIRUFDQFHUWKHUDS\&DQFHU6FL± 12. +HOG - 6FKXO]H2VWKRII . 3RWHQWLDO DQG FDYHDWV RI 75$,/ LQ FDQFHU WKHUDS\'UXJ5HVLVW8SGDW± 13. 6]OLV]ND ( 0D]XU % =\GRZLF] * &]XED =3 .UyO : 75$,/ LQGXFHGDSRSWRVLVDQGH[SUHVVLRQRIGHDWKUHFHSWRU75$,/5DQG75$,/ 5LQEODGGHUFDQFHUFHOOV)ROLD+LVWRFKHP&\WRELRO± 14. 6LHNLHUVNL-%DGDQLHG]LDáDQLDF\WRWRNV\F]QHJRVXEVWDQFMLFKHPLF]Q\FK 3RVW%LRO.RP± 15. 6WDĔF]\N 0 0DMVWHUHN , $SRSWR]D ± FHO XNLHUXQNRZDQHM WHUDSLL SU]HFLZQRZRWZRURZHM3RVW%LRO.RP±. 320. 16. &KLOPRQF]\N = 5HFHSWRU\ ĞPLHUFL ± FHO PROHNXODUQ\ OHNyZ SU]HFLZQRZRWZRURZ\FK*D]HWD)DUPDFHXW\F]QD± 17. 6WĊSLHĔ $ ,]GHEVND 0 *U]DQND $ 5RG]DMH ĞPLHUFL NRPyUNL 3RVW +LJ0HG'RVZ± 18. 6]OLV]ND(&]XED=30D]XU%3DUDG\V]$.URO:&KDOFRQHVDQG GLK\GURFKDOFRQHV DXJPHQW 75$,/PHGLDWHG DSRSWRVLV LQ SURVWDWH FDQFHU FHOOV0ROHFXOHV± 19. 6]OLV]ND( .URO: 7KH UROHRIGLHWDU\SRO\SKHQROV LQWXPRU QHFURVLV IDFWRUUHODWHG DSRSWRVLV LQGXFLQJ OLJDQG 75$,/

(81) LQGXFHG DSRSWRVLV IRU FDQFHUFKHPRSUHYHQWLRQ(XU-&DQFHU3UHY± 20. 7D\ORU 5$ 7RLYDQHQ 5 5LVEULGJHU *3 6WHP FHOOV LQ SURVWDWH FDQFHU WUHDWLQJ WKH URRW RI WKH SUREOHP (QGRFU 5HODW &DQFHU 5± 21. 6]OLV]ND ( &]XED =3 %URQLNRZVND - 0HUWDV $ 3DUDG\V] $ .URO :(WKDQROLF([WUDFWRI3URSROLV$XJPHQWV75$,/,QGXFHG$SRSWRWLF'HDWK LQ 3URVWDWH &DQFHU &HOOV (YLG %DVHG &RPSOHPHQW $OWHUQDW 0HG 22. 6]OLV]ND ( =\GRZLF] * 0L]JDOD ( .URO : $UWHSLOOLQ & GLSUHQ\OK\GUR[\FLQQDPLFDFLG

(82) VHQVLWL]HV/1&D3SURVWDWHFDQFHUFHOOVWR 75$,/LQGXFHGDSRSWRVLV,QW-2QFRO± 23. 0DUVWHUV 6$ 3LWWL 5$ 6KHULGDQ -3 $VKNHQD]L $ &RQWURO RI DSRSWRVLVVLJQDOLQJE\$SROLJDQG5HFHQW3URJ+RUP5HV± ± 24. 9RHONHO-RKQVRQ&75$,/PHGLDWHGVLJQDOLQJ LQ SURVWDWHEODGGHUDQG UHQDOFDQFHU1DW5HY8URO± 25. 1RUULV -6 +\HU 0/ 9RHONHO-RKQVRQ & /RZH 6/ 5XELQFKLN 6 'RQJ-<7KHXVHRI)DV/LJDQG75$,/DQG%D[LQJHQHWKHUDS\RISURVWDWH FDQFHU&XUU*HQH7KHU± 26. 9DQ2SKRYHQ$1J&33DWHO%%RQDYLGD%%HOOGHJUXQ$7XPRU QHFURVLV IDFWRUUHODWHG DSRSWRVLVLQGXFLQJ OLJDQG 75$,/

(83) IRU WUHDWPHQW RI SURVWDWH FDQFHU ILUVW UHVXOWV DQG UHYLHZ RI WKH OLWHUDWXUH 3URVWDWH &DQFHU 3URVWDWLF'LV± 27. -XQJ<++HR-/HH<-.ZRQ7..LP<+4XHUFHWLQHQKDQFHV 75$,/LQGXFHG DSRSWRVLV LQ SURVWDWH FDQFHU FHOOV YLD LQFUHDVHG SURWHLQ VWDELOLW\RIGHDWKUHFHSWRU/LIH6FL± 28. /L : =KDQJ ; 2OXPL $) 0* VHQVLWL]HV 75$,/UHVLVWDQW SURVWDWH FDQFHU FHOOV E\ DFWLYDWLQJ F)RVF-XQ KHWHURGLPHUV DQG UHSUHVVLQJ F)/,3 /

(84) &DQFHU5HV±.

(85) SZLAK TRAIL JAKO CEL TERAPII W RAKU PROSTATY. 29. *XVHYD 19 7DJKL\HY $) 5RNKOLQ 2: &RKHQ 0% 'HDWK UHFHSWRULQGXFHGFHOOGHDWKLQSURVWDWHFDQFHU-&HOO%LRFKHP± ± 30. &KZLDáNRZVND $ .XOEDFND - 6DF]NR - ĝPLHUü NRPyUHN QRZRWZRURZ\FK 8G]LDá UHDNFML IRWRG\QDPLF]QHM Z LQGXNFML DSRSWR]\ ZNRPyUNDFKQRZRWZRURZ\FK3RO0HUNXULXV]/HN± 31. 0DKDOLQJDP'6]HJH]GL( .HDQH0GH-RQJ66DPDOL $ 75$,/ UHFHSWRU VLJQDOOLQJ DQG PRGXODWLRQ $UH ZH RQ WKH ULJKW 75$,/" &DQFHU 7UHDW5HY± 32. $PP +0 2OLYHU 3* /HH &+ /L < %XFKVEDXP '- &RPELQHG PRGDOLW\WKHUDS\ZLWK 75$,/ RUDJRQLVWLFGHDWKUHFHSWRUDQWLERGLHV&DQFHU %LRO7KHU± 33. +XDQJ<6KHLNK0675$,/GHDWKUHFHSWRUVDQGFDQFHUWKHUDSHXWLFV 7R[LFRO$SSO3KDUPDFRO± 34. :X;;.DNHKL<(QKDQFHPHQWRIOH[DWXPXPDELQGXFHGDSRSWRVLVLQ KXPDQ VROLG FDQFHU FHOOV E\ &LVSODWLQ LQ FDVSDVHGHSHQGHQW PDQQHU &OLQ &DQFHU5HV± 35. 6KLPDGD 2 :X ; -LQ ; L ZVS +XPDQ DJRQLVWLF DQWLERG\ WR WXPRU QHFURVLV IDFWRUUHODWHG DSRSWRVLVLQGXFLQJ OLJDQG UHFHSWRU LQGXFHV F\WRWR[LFLW\ DQG DSRSWRVLV LQ SURVWDWH FDQFHU DQG EODGGHU FDQFHU FHOOV 8URORJ\± 36. .U]DNRZVNL0&KHPLRWHUDSLD UDND JUXF]RáXNURNRZHJR2QNRO3UDNW .OLQ± 37. 'RX ' 7DR : /L / 7KH HIIHFW RI SRO\VDFFKDULGH SHSWLGH DQG WD[RO RQ KXPDQ VROLG WXPRU WLVVXH LQ YLWUR - 0HG 3ODQW 5HV ± ± 38. )X</L6=X<0HGLFLQDOFKHPLVWU\RISDFOLWD[HODQGLWVDQDORJXHV &XUU0HG&KHP± 39. 7DEDF]DU 6 .RFHYD&K\áD $ 0DWF]DN . *ZRĨG]LĔVNL . 0ROHNXODUQH PHFKDQL]P\ DNW\ZQRĞFL SU]HFLZQRZRWZRURZHM WDNVDQyZ , 2GG]LDá\ZDQLHGRFHWDNVHOXQDPLNURWXEXOH3RVW+LJ0HG'RVZ ± 40. $EGXOOD $ .DSRRU $ (PHUJLQJ QRYHO WKHUDSLHV LQ WKH WUHDWPHQW RI FDVWUDWHUHVLVWDQWSURVWDWHFDQFHU&DQ8URO$VVRF-±. . 41. %RGQDU / :FLVáR * 0LHG]LĔVND0DFLHMHZVND 0 6]F]\OLN & 'RFHWDNVHO L SDNOLWDNVHO SRUyZQDQLH LFK EXGRZ\ IDUPDNRORJLL RUD] PHFKDQL]PyZRSRUQRĞFL:VSyáF]2QNRO± 42. 1LPPDQDSDOOL 5 3HUNLQV &/ 2UODQGR 0 2 %U\DQ ( 1JX\HQ ' %KDOOD .1 3UHWUHDWPHQW ZLWK SDFOLWD[HO HQKDQFHV DSR OLJDQGWXPRU QHFURVLV IDFWRUUHODWHG DSRSWRVLVLQGXFLQJ OLJDQGLQGXFHG DSRSWRVLV RI SURVWDWH FDQFHU FHOOV E\ LQGXFLQJ GHDWK UHFHSWRUV DQG SURWHLQ OHYHOV &DQFHU5HV± 43. &HUVRVLPR 5- 1HZ DJHQWV IRU WKH PDQDJHPHQW RI FDVWUDWLRQUHVLVWDQW SURVWDWHFDQFHU$QQ3KDUPDFRWKHU± 44. 0HGLDYLOOD9DUHOD 0 3DFKHFR )- $OPDJXHO ) L ZVS 'RFHWD[HO LQGXFHGSURVWDWHFDQFHUFHOOGHDWKLQYROYHVFRQFRPLWDQWDFWLYDWLRQRIFDVSDVH DQG O\VRVRPDO SDWKZD\V DQG LV DWWHQXDWHG E\ /('*)S 0RO &DQFHU 45. <RR-3DUN66/HH<-3UHWUHDWPHQWRIGRFHWD[HOHQKDQFHV75$,/ PHGLDWHG DSRSWRVLV LQ SURVWDWH FDQFHU FHOOV - &HOO %LRFKHP ± 46. )R[ (- 0HFKDQLVP RI DFWLRQ RI PLWR[DQWURQH 1HXURORJ\ ± 47. 7D\ORU '- 3DUVRQV &( +DQ + -D\DUDPDQ $ 5HJH . 3DUDOOHO VFUHHQLQJRI)'$DSSURYHGDQWLQHRSODVWLFGUXJVIRULGHQWLI\LQJVHQVLWL]HUVRI 75$,/LQGXFHGDSRSWRVLVLQFDQFHUFHOOV%0&&DQFHU 48. *DUFLD -$ 5LQL %, &DVWUDWLRQUHVLVWDQW SURVWDWH FDQFHU PDQ\ WUHDWPHQWV PDQ\RSWLRQV PDQ\FKDOOHQJHVDKHDG &DQFHU± ± 49. -HUHF]HN)RVVD %$ 5ROD UDGLRWHUDSLL Z OHF]HQLX UDND JUXF]RáX NURNRZHJR:VSyáF]2QNRO± 50. (ULNVVRQ ' 6WLJEUDQG 7 5DGLDWLRQLQGXFHG FHOO GHDWK PHFKDQLVPV 7XPRXU%LRO± 51. 9HUKHLM 0 &OLQLFDO ELRPDUNHUV DQG LPDJLQJ IRU UDGLRWKHUDS\LQGXFHG FHOOGHDWK&DQFHU0HWDVWDVLV5HY± 52. 6KDQNDU66LQJK756ULYDVWDYD5.,RQL]LQJUDGLDWLRQHQKDQFHVWKH WKHUDSHXWLF SRWHQWLDO RI 75$,/ LQ SURVWDWH FDQFHU LQ YLWUR DQG LQ YLYR ,QWUDFHOOXODUPHFKDQLVPV3URVWDWH±. 321.

(86)