ORİJİNAL ARAŞTIRMA Radiopharmaceutical Model Using Tc-DMSA to Evaluate Amifostine Protection Against Cisplatin Nephrotoxicity in Rats Yakup YÜREKLİ, MD, a Perihan ÜNAK, b Türkan ERTAY, c Fazilet Zümrüt BİBER MÜFTÜLER, b Emin İlker MEDİNE, b Çiğdem ACAR b a Department of Nuclear Medicine, Adnan Menderes University Faculty of Medicine, Aydın, b Department of Nuclear Applications, Ege University Institute of Nuclear Sciences, c Department of Nuclear Medicine, Dokuz Eylul University Faculty of Medicine, İzmir Ge liş Ta ri hi/re ce i ved: 25.11.2010 Ka bul Ta ri hi/ac cep ted: 19.12.2010 This study was presented as poster at 18 th Annual Congress of the EANM, Istanbul 2005. Ya zış ma Ad re si/cor res pon den ce: Yakup YÜREKLİ, MD Adnan Menderes University Faculty of Medicine, Department of Nuclear Medicine, Aydın, TÜRKİYE/TURKEY yyurekli@adu.edu.tr ABS TRACT Ob jec ti ve: The aim of our study was to use an in vi vo ra di op har ma ce u ti cal mo del to in ves - ti ga te the cytop ro tec ti ve ef fect of ami fos ti ne aga inst cisp la tin-in du ced nep hro to xi city. Ma te ri al and Met - hods: Ma le Wis tar rats we re di vi ded in to fo ur gro ups of six ani mals each: 1) Sa li ne (con trol); 2) Ami fos ti ne (AMI; 200 mg /kg in tra pe ri to ne ally); 3) Cisp la tin (CIS; 5 mg/kg in tra pe ri to ne ally); 4) Cisp la tin plus ami - fos ti ne (CIS + AMI). Ami fos ti ne was in jec ted 30 mi nu tes be fo re cisp la tin in Gro up 4. Tc-DMSA, 7.4 MBq/0.2 ml, was in jec ted thro ugh the ta il ve in 72 ho urs af ter the drug ad mi nis tra ti on. Blo od samp les we - re ob ta i ned for the as says of plas ma cre a ti ni ne and blo od ure a nit ro gen (BUN). Rats we re kil led and the kid neys we re re mo ved by dis sec ti on 120 mi nu tes af ter the in jec ti on of the ra di op har ma ce u ti cal. Ra di o - ac ti vity in each or gan samp le was co un ted using a Cd(Te) de tec tor equ ip ped with a RAD 501 sing lechan nel analy zer and a %ID/g ac ti vity was cal cu la ted by di vi ding the ac ti vity in each kid ney by the to tal ac ti vity in jec ted and the mass of the or gan. Re sults: Tc-DMSA up ta ke as %ID/g was 8.9938 ± 1.5220 and 6.4898 ± 1.4091 in the con trol and AMI gro ups res pec ti vely. Cisp la tin ad mi nis tra ti on re sul ted a sig - ni fi cant dec re a se in %ID/g (1.5913 ± 0.4566) (p<0.01). Ami fos ti ne ad mi nis tra ti on 30 mi nu tes be fo re cisp - la tin in jec ti on re sul ted a sig ni fi cant in cre a se in %ID/g (7.3670 ± 2.6090) com pa red to cisp la tin-tre a ted rats (p<0.002). A mar ked in cre a se in plas ma BUN and cre a ti ni ne in di ca ting nep hro to xi city and acu te re nal fa i lu re was ob ser ved in the cisp la tin-tre a ted gro up. Conc lu si on: The re sults sho wed that ami fos ti ne sig - ni fi cantly at te nu a ted cisp la tin-in du ced nep hro to xi city. We conc lu de that this ra di op har ma ce u ti cal mo - del is ab le to de mons tra te cisp la tin nep hro to xi city and ami fos ti ne pro tec ti on aga inst it. Key Words: Radiopharmaceuticals; technetium Tc dimercaptosuccinic acid; amifostine; cisplatin ÖZET Amaç: Ça lış ma nın ama cı sisp la ti nin ne den ol du ğu nef ro tok si si te ye kar şı ami fos ti nin ko ru yu cu et - ki si ni bir in vi vo rad yo far ma sö tik mo del kul la na rak araş tır mak tı. Ge reç ve Yön tem ler: Er kek Wis tar sı - çan la rı her bi ri 6 hay van dan olu şan 4 gru ba ay rıl dı: 1) Se rum fiz yo lo jik (kon trol); 2) Ami fos tin (AMI; 200 mg /kg in tra pe ri to ne al); 3) Sisp la tin (CIS; 5 mg/kg in tra pe ri to ne al); 4) Sisp la tin ar tı ami fos tin (CIS + AMI). Grup 4 te ami fos tin sisp la tin den 30 da ki ka on ce en jek te edil di. İlaç lar ve ril dik ten son ra ki 72. sa at te kuy - ruk ve nin den plaz ma BUN ve kre a ti nin dü zey le ri ni be lir le mek ama cıy la kan ör nek le ri alın dık tan son ra 7.4 MBq/0.2 ml Tc-DMSA en jek te edil di. Rad yo far ma sö ti ğin en jek si yo nun dan 120 da ki ka son ra sı çanlar öl dü rül dü ve böb rek le ri çı ka rıl dı. Her bir do ku ör ne ğin de ki rad yo ak ti vi te RAD 501 tek ka nal lı ana li - zö rü olan bir Cd(Te) de dek tör le sa yıl dı ve her bir böb rek te ki ak ti vi te en jek te edi len to tal ak ti vi te ve or ga nın kit le si ne bö lü ne rek bir %ID/gr ak ti vi te si he sap lan dı. Bul gu lar: Kon trol ve AMI grup la rın da %ID/g ola rak Tc-DMSA up ta ke i sı ra sıy la 8.9938 ± 1.5220 ve 6.4898 ± 1.4091 idi. Sisp la tin uy gu la ma sı CIS gru bun da %ID/g de an lam lı azal ma ya ne den ol du (1.5913 ± 0.4566) (p<0.01). Sisp la tin uy gu la ma sın dan 30 da ki ka on ce ami fos tin ve ril me si sa de ce sisp la tin ve ri len grup la kı yas lan dı ğın da %ID/g de an lam lı ar tı şa (7.3670 ± 2.6090) ne den ol du (p< 0.002). Sisp la tin ve ri len grup ta plaz ma BUN ve kre a ti nin dü zey le rin de nef ro tok si si te ve akut re nal yet mez li ği ni gös te ren be lir gin ar tış lar göz len di. So nuç: Bul gu lar ami fos ti nin sisp la ti nin ne den ol du ğu nef ro tok si si te yi an lam lı dü zey de azalt tı ğı nı gös ter mek tek te dir. Bu rad ya far ma - sö tik mo del le sisp la tin nef ro tok si si te si ve ami fos ti nin ko ru yu cu et ki si gös te ri le bil miş tir. Anah tar Ke li me ler: Radyofarmasötikler; teknesyum Tc dimerkaptosüksinik asid; amifostin; sisplatin Cop yright 2010 by Tür ki ye Nükleer Tıp Derneği Turk J Nucl Med 2010;19(3):105-9 Turk J Nucl Med 2010;19(3) 105
Yakup YÜREKLİ et al RADIOPHARMACEUTICAL MODEL USING Tc-DMSA TO EVALUATE AMIFOSTINE... isp la tin is an ef fec ti ve an ti ne op las tic agent in the tre at ment of a va ri ety of tu mors. Its cyto to xic ac ti vity is tho ught to be me di a ted thro ugh DNA in tras trand cross lin king and ad duct for ma ti on. Cisp la tin in du ces sig ni fi cant oto to xi city, ne u ro to xi city and nep hro to xi city. Do se-re la ted nep hro to xi city has be en the ma jor do se-li mi ting to xi city of cisp la tin. Alt ho ugh the pre ci se mec ha - nism of cisp la tin nep hro to xi city is not known, the si te of ma xi mum cisp la tin da ma ge is the pro xi mal tu bu les. 1,2 Ini ti al pro xi mal tu bu lar in jury is fol lo - wed by dis rup ti on of glo me ru lar fil tra ti on and impa i red dis tal tu bu lar func ti on, and nep hro to xi city is ma ni fes ted as a re duc ti on in glo me ru lar fil tra ti on ra te and a ri sing se rum cre a ti ni ne le vel. Va ri o us met hods and drugs ha ve be en tes ted to pre vent cisp la tin-in du ced nep hro to xi city. 3 Cytop - ro tec ti ve agents which are mostly fre e ra di cal sca v- en gers and an ti o xi dants ha ve be en in ten si vely stu di ed for pro tec ti on aga inst an ti ne op las tic drugin du ced to xi ci ti es inc lu ding nep hro to xi city. Ami - fos ti ne was re com men ded in the Ame ri can So ci ety of Cli ni cal On co logy Cli ni cal Prac ti ce Gu i de li nes for the Use of Che mot he rapy and Ra di ot he rapy Pro tectants for pre ven ti on of cisp la tin-re la ted to xi city. 4 Ami fos ti ne (AMI, WR-2721, Eth yol) is a prodrug that forms an ac ti va ted fre e thi ol (WR-1065) thro ugh dep hosp hory la ti on by mem bra ne-bo und al ka li ne phosp ha ta se in nor mal cells. 5 AMI se lec ti - vely pro tects nor mal cells from to xic ef fects of anti ne op las tic agents by sca ven ging fre e ra di cals, do na ting hydro gen ions, and bin ding to ac ti ve me - ta bo li tes of an ti ne op las tic agents. 6 The re is a gro - wing amo unt of evi den ce of its abi lity to se lec ti vely pro tect al most all nor mal tis su es ex cept the cen tral ner vo us system, but it has not be en shown to protect ne op las tic tis su es from the cyto to xic ef fects of che mot he ra pe u tic agents or ra di a ti on the rapy. 7 Ho - we ver, ar gu ment still con ti nu es abo ut its cli ni cal use. 8 Ra di op har ma ce u ti cals are used for the di ag no - sis and the rapy of di se a ses. They are usu ally ad mi - nis te red in tra cer qu an ti ti es and ex hi bit no phar ma co lo gi cal ef fect. Con si de rab le evi den ce has be en ac cu mu la ted that the bi o dis tri bu ti on or pharma co ki ne tics of ra di op har ma ce u ti cals might be alte red by a va ri ety of drugs. 9, 10 The al te ra ti ons may be in du ced as a re sult of phar ma co lo gi cal ac ti on of the drug, physi coc he mi cal in te rac ti on bet we en the drug and the ra di op har ma ce u ti cal, or drug-in du - ced to xi city. 11 Ra di op har ma ce u ti cals can be used li - ke wi se to eva lu a te the ef fect of the drug by qu an ti fi ca ti on of the al te ra ti ons in the bi o dis tri bu - ti on of the ra di op har ma ce u ti cal. Tc-DMSA (me so-2,3-di mer cap to suc ci nic acid) has be en used for func ti o nal ima ging of the pro xi mal re nal tu bu lar mass for thirty ye ars. 12, 13 It is ac cu mu la ted in the re nal tu bu lar cells by pe ri tu - bu lar up ta ke which may be me di a ted by the or ga - nic ani on trans port system. 14 Its up ta ke de pends on re nal blo od flow and pro xi mal tu bu lar cell membra ne trans port func ti on. It was de mons tra ted that Tc-DMSA was use ful in the study of re nal tu bu - lar dysfunc ti on in rats and used cli ni cally in pa ti - ents with pro xi mal tu bu lar dysfunc ti on. 15,16 In this study, we in ves ti ga ted the po ten ti al pro tec ti ve ef fect of ami fos ti ne aga inst cip la tin nep - hro to xi city by using a Tc-DMSA ra di op har ma - ce u ti cal mo del. Sin ce the re are many pro po sed cytop ro tec ti ve com po unds, this simp le in vi vo expe ri men tal mo del may ser ve as an im por tant to ol to eva lu a te and com pa re the cytop ro tec ti ve ef fects of the se agents. MA TE RI AL AND MET HODS Ma le Wis tar al bi no rats, we ig hing 190-260 g, we re pro vi ded by the Ex pe ri men tal Sur gery and Re se - arch La bo ra to ri es of Ege Uni ver sity. Rats we re randomly di vi ded in to fo ur gro ups: 1) Sa li ne (con trol; 1 ml in tra pe ri to ne ally) (n= 6); 2) Cisp la tin (CIS; 5 mg/kg in tra pe ri to ne ally) (n= 6); 3) Ami fos ti ne (AMI; 200 mg /kg in tra pe ri to ne ally) (n= 6); 4) Cisp la tin plus ami fos ti ne (CIS + AMI) (n= 6). Ami fos - ti ne was in jec ted 30 mi nu tes be fo re cisp la tin in Gro up 4. The study pro to col was ap pro ved by the Ins ti tu ti o nal Ani mal Re vi ew Com mit te e of Ege Uni ver sity and all ani mals ha ve re ce i ved hu ma ne ca re in comp li an ce with the Gu i de for the Ca re and Use of La bo ra tory Ani mals. Cisp la tin (DBL, 10 mg/10ml vi al, FH Fa ul ding & Co Li mi ted Aus tra li a) and ami fos ti ne (Eth yol, 500 mg, TR Er kim Ltd Sti) we re purc ha sed com- 106 Turk J Nucl Med 2010;19(3)
RADIOPHARMACEUTICAL MODEL USING Tc-DMSA TO EVALUATE AMIFOSTINE... Yakup YÜREKLİ et al mer ci ally. Ami fos ti ne was dis sol ved in 9.7 ml of do ub le dis til led wa ter. Tc, as so di um per tech ne ta te, was elu ted from a 99 Mo/ Tc ge ne ra tor (Mon rol A.Ş. Is tan bul, Tur key) just be fo re the ra di o la bel ling pro ce du re. DMSA (Tech nes can, Mal linc krodt Me di cal B.V Hol land) was purc ha sed as a fre e ze-dri ed com mer - ci al kit con ta i ning 1.2 mg di mer cap to suc ci nic acid, 0.3 mg stan no us chlo ri de dehy dra te and 30 mg ino si tol. Tc-DMSA was pre pa red by ad ding 740 MBq of Tc per tech ne ta te to 3 ml of sa li ne to the kit. Qu a lity con trol pro ce du res we re per for med accor ding to the ma nu fac tu rer s ins truc ti ons af ter 15 mi nu tes in cu ba ti on at ro om tem pe ra tu re. La be ling ef fi ci ency was gre a ter than 95%. Tc-DMSA, 7.4 MBq/0.2 ml, was ad mi nis te - red thro ugh the ta il ve in. Rats we re kil led by he art punc tu re un der in ten se et her at mosp he re, and the kid neys we re re mo ved by dis sec ti on two ho urs af - ter the ra di op har ma ce u ti cal in jec ti on. Samp les of kid neys we re we ig hed in pre-we ig hed con ta i ners. Ra di o ac ti vity in each or gan samp le was co un ted using a Cd(Te) de tec tor equ ip ped with a RAD 501 sing le-chan nel analy zer. The ac ti vity was ex pres - sed as a per cen ta ge of the in jec ted do se per gram of tis su e (%ID/g). The %ID/g ac ti vity was cal cu la ted by di vi ding the ac ti vity in each or gan by to tal ac ti - vity in jec ted and the mass of the or gan. The BUN and cre a ti ni ne le vels in se rum we re me a su red with an au to a naly ser using com mer ci al di ag nos tic kits (Sig ma-al drich Che mi e, Ger many). Da ta we re analy zed using a com mer ci al softwa re pac ka ge (SPSS for Win dows v.10, Chi ca go, USA). Dif fe ren ces among the %ID/g ac ti vi ti es of the kid neys in the fo ur gro ups we re analy zed by the non pa ra met ric Krus kal-wal lis test. Da ta we re pre sen ted as the me an ± SD. Mann-Whit ney U test was used to com pa re two in de pen dent samp les. All sta tis ti cal tests we re 2-ta i led and dif fe ren ces we re eva lu a ted at the 5% le vel of sig ni fi can ce. RE SULTS In tra pe ri to ne al in jec ti on of cisp la tin at a sing le do - se of 5 mg/kg body we ight re sul ted in acu te re nal fa i lu re as in di ca ted by sig ni fi cant in cre a se in plas - ma BUN and cre a ti ni ne le vels com pa red with controls (p<0.001). Ami fos ti ne ad mi nis te red 30 mi nu - tes be fo re cisp la tin pre ven ted the cisp la - tin-in du ced ele va ti ons in BUN and cre a ti ni ne (Tab le 1). The per cen ta ge of the in jec ted do se per gram of kid ney tis su e (%ID/g) in sa li ne (con trol), AMI, CIS and AMI+CIS gro ups are shown in Fi gu re 1. Tc-DMSA up ta ke per gram tis su e of the kid ney as %ID/g was 8.9938 ± 1.5220 and 6.4898 ± 1.4091 in the con trol and AMI gro ups res pec ti vely. Cisp - la tin led to a sig ni fi cant dec re a se in tu bu lar up ta ke of Tc-DMSA. %ID/g was the lo west of all the gro ups, 1.5913 ± 0.4566 (p< 0.01), in the cisp la tin gro up. Ami fos ti ne ad mi nis tra ti on 30 mi nu tes be fo - re cisp la tin in jec ti on re sul ted a sig ni fi cant in cre a se in %ID/g (7.3670 ± 2.6090) com pa red to tho se of cisp la tin-tre a ted rats (p<0.002). TABLE 1: Effect of cisplatin (CIS), amifostine (AMI) and their combination on the levels of blood urea nitrogen (BUN) and plasma creatinine. Groups BUN, mg/dl Creatinine, mg/dl Control (saline) 35.00 ± 6.2 0.43 ± 0.08 CIS 189.31 ± 49.7* 3.17 ± 1.8* AMI 44.65 ± 5.0 0.51 ± 0.7 AMI + CIS 37.67 ± 3.08** 0.64 ± 1.7** Values are means ± SEM; * significant change from control (p < 0.001) and ** significant change from CIS (p < 0.001). FIGURE 1: Percentage of injected activity per gram of kidney (%ID/g) in the saline (control), AMI (amifostine), CIS (cisplatin) and CIS+AMI (cisplatin plus amifostine) groups. Values are means ± SEM. Turk J Nucl Med 2010;19(3) 107
Yakup YÜREKLİ et al RADIOPHARMACEUTICAL MODEL USING Tc-DMSA TO EVALUATE AMIFOSTINE... DIS CUS SI ON We used an in vi vo ra di op har ma ce u ti cal mo del using Tc-DMSA to test the pro tec ti ve ef fect of ami fos ti ne aga inst acu te cisp la tin nep hro to xi city. This ra di op har ma ce u ti cal mo del is ba sed on the use of a ra di op har ma ce u ti cal which is spe ci fic to the or gan of in te rest to de mons tra te the drug ef fect on the bi o dis tri bu ti on of the ra di op har ma ce u ti cal. It is well-known that bi o dis tri bu ti on of the ra di op - har ma ce u ti cals may be al te red as a re sult of pharma co lo gi cal ac ti on of the drug, physi coc he mi cal in te rac ti on bet we en the drug and ra di op har ma ce - u ti cal or drug-in du ced to xi city. 11 The re fo re it is rati o nal to use ra di op har ma ce u ti cals to mo ni tor the drug s ef fect. In tra pe ri to ne al ad mi nis tra ti on of a sing le do se of 5 mg/kg cisp la tin in du ced a sig ni fi cant dec re a se in the up ta ke of Tc-DMSA in the rats kid neys com pa red to the con trol gro up (p<0.001) con sis tent with tu bu lar in jury and nep hro to xi city as in di ca - ted by the ele va ted BUN and cre a ti ni ne le vels. In the gro up in which rats we re pret re a ted with 200 mg/kg ami fos ti ne be fo re cisp la tin in jec ti on, no signi fi cant dec re a se in the up ta ke of Tc-DMSA was ob ser ved, which is con cor dant with the pro tec ti ve ef fect of ami fos ti ne. Alt ho ugh the re was a dec re a - sed %ID/g in the ami fos ti ne-alo ne gro up com pa red to the con trol gro up, the dif fe ren ce was not sig ni - fi cant. As it is con cor dant with BUN and cre a ti ni - ne le vels, this may be du e to a mild to xic ef fect of ami fos tin it self on tu bu lar cells. 17, 18 Ab sen ce of his - to pat ho lo gi cal eva lu a ti on of the kid neys is the ma - jor li mi ta ti on of the study. Ad di ti o nal do se/res pon se stu di es can cla rify the si tu a ti on. Our re sults con fir med the prec li ni cal and cli ni cal stu - di es in di ca ting the pro tec ti ve ef fect of ami fos ti ne aga inst cisp la tin-in du ced to xi city. 19-22 Tc-DMSA is the drug of cho i ce for ima ging func ti o nal re nal cor ti cal mass. It con cen tra tes in the cytop lasm of the pro xi mal tu bu lar cells. 23 Gentamy cin and cisp la tin nep hro to xi city had be en shown ex pe ri men tally to im pa ir Tc-DMSA re - nal up ta ke. 24,25 Tc-DMSA scin tig raphy has be en used cli ni cally with suc cess to di ag no se and mo ni - tor ifos fa mid-in du ced tu bu lar dysfunc ti on and cisp la tin and cisp la tin/ifos fa mid nep hro to xi city in 26, 27 chil dren. The re are se ve ral stu di es that in ves ti ga te the to xi co lo gi cal ef fects of che mot he ra pe u tics using radi op har ma ce u ti cals on the ba sis of al te ra ti ons in the bi o dis tri bu ti on of the ra di op har ma ce u ti cals ca - u sed by the drug. In the se stu di es, the aut hors obser ved sig ni fi cant al te ra ti ons in the bi o dis tri bu ti on of the ra di op har ma ce u ti cals and exp la i ned the se alte ra ti ons by the phar ma co ki ne tic, phar ma co lo gi cal and to xic ef fects of the drugs. 28-30 Cytop ro tec ti ve agents ha ve be en in ten si vely stu di ed re cently, be ca u se the si de ef fects of an ti - can cer the ra pi es re ma in a con si de rab le obs tac le to tre at ment suc cess des pi te prog ress in the dis co very of new an ti ne op las tic agents. Li fe-thre a te ning comp li ca ti ons or ir re ver sib le tis su e da ma ge that seve rely af fect qu a lity of li fe are da ily chal len ges in cli ni cal on co logy. Mo re o ver, do se-li mi ting to xi ci - ti es pre vent the app li ca ti on of ap prop ri a te the ra - pe u tic sche du les and mask the cu ra ti ve po ten ti al of the ava i lab le agents aga inst can cer. Cytop ro tec ti ve agents are im por tant in terms of pre ven ting the se si de ef fects and im pro ving the the ra pe u tic po ten ti - al of the an ti ne op las tic drugs. The re are many po ten ti al cytop ro tec ti ve agents pro po sed which are mostly fre e ra di cal sca - ven gers and an ti o xi dants, and it ne ces si ta tes sop - his ti ca ted tech ni qu es to de mons tra te the ef fi cacy of an agent for cytop ro tec ti on. We sug gest that this simp le in vi vo ra di op har ma ce u ti cal mo del can ma - ke a va lu ab le con tri bu ti on to de mons tra ti on and com pa ri son of the ef fi cacy of po ten ti al cytop ro tec - ti ve agents. 108 Turk J Nucl Med 2010;19(3)
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