{"id":10121,"date":"2020-04-23T03:57:12","date_gmt":"2020-04-23T00:57:12","guid":{"rendered":"https:\/\/www.synevo.ro\/product\/timidinkinaza\/"},"modified":"2025-02-07T15:45:21","modified_gmt":"2025-02-07T13:45:21","slug":"timidinkinaza","status":"publish","type":"product","link":"https:\/\/old.synevo.md\/ru\/shop\/timidinkinaza\/","title":{"rendered":"\u0422\u0438\u043c\u0438\u0434\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u0430"},"content":{"rendered":"

Informa<\/em><\/strong>\u0163<\/em><\/strong>ii generale<\/em><\/strong><\/p>\n

Timidin kinaza<\/em> este o enzim\u0103 citosolic\u0103 cheie \u00een calea de salvare a ADN-ului, cataliz\u00e2nd transferul grupului fosfat terminal de la nivelul ATP la grupul 5`hidroxil al deoxitimidinei pentru a produce deoxitimidin\u0103 monofosfat, care este apoi \u00eencorporat\u0103 \u00een ADN19<\/sup>. Sinteza de novo<\/em> a timidinei monofosfat este \u00een mod normal catalizat\u0103 de timidilat sintetaz\u0103 din deoxiuridin\u0103 monofosfat, \u00een prezen\u0163a acidului folic \u015fi vitaminei B12. TK utilizeaz\u0103 fie timidin\u0103 exogen\u0103 din alimente, fie timidina endogen\u0103 eliberat\u0103 prin degradarea unui substrat. Din acest motiv a fost desemnat\u0103 ca o enzim\u0103 de salvare. TK este o enzim\u0103 implicat\u0103 \u00een sinteza acizilor nucleici \u015fi, prin urmare, considerat\u0103 un important marker de proliferare, \u00een mod particular \u00een celulele tumorale18<\/sup>.<\/p>\n

Exist\u0103 dou\u0103 izoforme ale enzimei \u00een celulele umane: TK1<\/em> \u2013 citosolic\u0103, g\u0103sit\u0103 numai \u00een celulele proliferante, produc\u0163ia sa fiind restric\u0163ionat\u0103 \u00een faza S a ciclului celular asociat\u0103 cu diviziunea celular\u0103, \u015fi TK2<\/em> \u2013 mitocondrial\u0103, independent\u0103 de fazele ciclului celular \u015fi a c\u0103rei concentra\u0163ie nu este corelat\u0103 cu proliferarea.<\/p>\n

TK1 este forma predominant\u0103 \u00een ser \u015fi este un homodimer sau homotetramer alc\u0103tuit din subunit\u0103\u0163i monomerice de 24kDa. TK1 poate fosforila analogi pirimidinici importan\u0163i clinic, incluz\u00e2nd 5-fluoro-2`- dideoxitimidina \u015fi 3`-azido-2`,3`-dideoxitimidina (AZT)19<\/sup>.<\/p>\n

Nivelul TK \u00een ser sau plasm\u0103 este at\u00e2t de mic, \u00eenc\u00e2t m\u0103surarea sa este bazat\u0103 pe activitatea enzimatic\u0103, testele comerciale utiliz\u00e2nd pentru aceasta analogi ai substratului. Determinarea TK \u00een ser s-a f\u0103cut ini\u0163ial printr-o tehnic\u0103 radioenzimatic\u0103 (REA), dificult\u0103\u0163ile tehnice \u015fi folosirea radioactivit\u0103\u0163ii f\u0103c\u00e2nd ca acest test s\u0103 nu fie larg acceptat. Mai recent au fost dezvoltate \u015fi tehnici nonizotopice, cum ar fi CLIA care a demonstrat o corela\u0163ie excelent\u0103 cu tehnologia standard REA. De asemenea metodele actuale permit determinarea activit\u0103\u0163ii enzimatice citosolice a TK, dar exist\u0103 \u015fi metode care determin\u0103 cantitatea, mai degrab\u0103 dec\u00e2t activitatea, TK \u00een materialele biologice, precum \u015fi metode imunohistochimice pentru TK6;19<\/sup>.<\/p>\n

TK a fost cel mai larg utilizat\u0103 clinic \u00eentre 1980 \u015fi 2000, deoarece determinarea nivelurilor serice sau citosolice a continuat metodele de \u00eencorporare a TK pentru monitorizarea activit\u0103\u0163ii proliferative a \u0163esuturilor. \u00cen anii urm\u0103tori s-a \u00eenregistrat o reducere considerabil\u0103 a aplica\u0163iilor clinice ale TK \u00een favoarea markerilor tumorali lega\u0163i de tipul histologic al tumorii (CA19-9, CA15-3) sau markerilor cu specificitate de organ (PSA), iar markerii de proliferare au continuat s\u0103 fie utiliza\u0163i \u00een special \u00een hematologie. Aplicarea sa \u00een practica clinic\u0103 a revenit \u00een jurul lui 2003 \u015fi de atunci a fost folosit\u0103 mai larg19<\/sup>.<\/p>\n

TK reprezint\u0103 \u00een prezent un marker tumoral secundar util \u00een principal pentru determinarea naturii agresive a tumorii \u015fi pentru monitorizarea anumitor cancere \u015fi a terapiei. A fost ar\u0103tat c\u0103 nivelul seric al TK1 la pacien\u0163i cu diferite forme de cancer se coreleaz\u0103 cu stadiul clinic al bolii, iar m\u0103sur\u0103tori repetate reflect\u0103 remisiuni \u015fi rec\u0103deri18;19<\/sup>.<\/p>\n

\u041f\u0440\u0438 bolile hematologice<\/span><\/strong>, a c\u0103ror caracteristic\u0103 principal\u0103 este proliferarea, TK \u00ee\u015fi g\u0103se\u015fte o aplica\u0163ie larg\u0103.<\/p>\n

\u25aa \u00cen leucemia limfatic\u0103 cronic\u0103<\/span> (CLL) prognosticul \u015fi evolu\u0163ia clinic\u0103 sunt heterogene. \u00cen timp ce unii pacien\u0163i pot avea o speran\u0163\u0103 de via\u0163\u0103 normal\u0103 f\u0103r\u0103 s\u0103 necesite tratament, al\u0163ii pot deceda cu boal\u0103 rezistent\u0103 la medicamente \u00een doi ani de la prezentare. Datorit\u0103 acestei variabilit\u0103\u0163i, \u00een ultimii ani mai mul\u0163i parametri clinici \u015fi hematologici au fost evalua\u0163i ca posibili indicatori ai prognosticului. Ace\u015ftia includ parametrii clinici (v\u00e2rsta, sexul, indicele de performan\u0163\u0103), parametrii de laborator care reflect\u0103 \u00eenc\u0103rc\u0103tura tumoral\u0103 sau activitatea bolii (num\u0103rul de limfocite, nivelul LDH, pattern-ul infiltr\u0103rii medulare, timpul de dublare a limfocitelor), iar mai recent au fost identifica\u0163i o serie de parametri cu valoare prognostic\u0103 mai mare, incluz\u00e2nd markeri serici (CD23 solubil, \u03b22<\/sub>-microglobulina sau TK), markeri genetici ai celulelor tumorale (abera\u0163ii genomice, anomalii genice, statusul muta\u0163ional al segmentelor variabile ale genei lan\u0163ului greu de imunoglobulin\u0103) sau markeri surogat ai acestor factori (CD38 \u015fi ZAP-70)6<\/sup>.<\/p>\n

Nivelul TK reflect\u0103 activitatea proliferativ\u0103 a celulelor leucemice, corel\u00e2ndu-se at\u00e2t cu stadiul Ray\/Binet c\u00e2t \u015fi cu statusul bolii, f\u0103c\u00e2nd distinc\u0163ia \u00eentre indolent \u015fi agresiv, nivelele sale asociindu-se cu alte aspecte care arat\u0103 \u00eenc\u0103rc\u0103tura tumoral\u0103 (gradul leucocitozei, limfocitozei, celularitatea medular\u0103) \u015fi cu al\u0163i indicatori ai turn-over-ului celulelor tumorale (\u03b22<\/sub>-microglobulina, LDH)2<\/sup>.<\/p>\n

\u00cen plus studiile au ar\u0103tat c\u0103 TK are semnifica\u0163ie prognostic\u0103, astfel c\u0103 poate fi un predictor independent al duratei intervalului f\u0103r\u0103 progresie a bolii \u015fi permite definirea CLL smoldering \u015fi non-smoldering \u00een stadiul Binet A11;19<\/sup>.<\/p>\n

Hallek et al.<\/em> au studiat valoarea prognostic\u0103 a TK la pacien\u0163i netrata\u0163i cu CLL stadiul Binet A. Din 22 parametri studia\u0163i numai 3 au furnizat informa\u0163ii prognostice independente asupra supravie\u0163uirii f\u0103r\u0103 progresie: TK >7.1 U\/L, prezen\u0163a limfadenopatiei \u015fi un num\u0103r de leucocite >75000\/\u03bcL. \u00cen plus TK adaug\u0103 informa\u0163ie prognostic\u0103 independent\u0103 privind definirea CLL smoldering \u015fi non-smoldering \u00een stadiul Binet A. Astfel, separ\u00e2nd pacien\u0163ii din grupul non-smolderig stadiul A \u00een dou\u0103 subgrupuri pe baza valorii TK, cei cu un nivel al TK >7.1 U\/L au avut o supravie\u0163uire f\u0103r\u0103 progresie median\u0103 de 8 luni, fa\u0163\u0103 de pacien\u0163ii cu nivelul TK \u2264 7.1 U\/L la care supravie\u0163uirea f\u0103r\u0103 progresie a fost mult mai lung\u0103, de 49 luni, similar\u0103 cu cea a pacien\u0163ilor smoldering (42 luni)19<\/sup>.<\/p>\n

\u00cen studiul lor Raimondo et al.<\/em> au ar\u0103tat c\u0103 TK este un indicator prognostic privind r\u0103spunsul la tratament \u015fi supravie\u0163uirea, astfel c\u0103 83% din pacien\u0163ii cu nivelul TK <10 U\/L au r\u0103spuns la tratamentul cu fludarabin\u0103, fa\u0163\u0103 de 45% din pacien\u0163ii cu nivelul TK >10 U\/L, iar rata supravie\u0163uirii mediane a fost de 65% la pacien\u0163ii cu nivelul TK <10 U\/L, fa\u0163\u0103 de 22% la cei cu nivelul TK >10 U\/L. Astfel pacien\u0163ii cu un nivel TK >10 U\/L prezint\u0103 un prognostic nefavorabil \u015fi trebuie considera\u0163i pentru un tratament agresiv19<\/sup>.<\/p>\n

\u00cen CLL lipsa muta\u0163iilor genei regiunii variabile a imunoglobilinei (IgV\u0417<\/sub>) este asociat\u0103 cu un prognostic marcat nefavorabil chiar \u015fi la pacien\u0163ii \u00een stadiul A, dar secven\u0163ierea genei IgV\u0417<\/sub> nu este disponibil\u0103 \u00een majoritatea laboratoarelor, astfel c\u0103 s-ar dori un surogat valid \u015fi u\u015for de efectuat. Magnac et al.<\/em> au ar\u0103tat c\u0103 un nivel al TK >15 U\/L este un predictor independent puternic al statusului muta\u0163ional al genei IgV\u0417<\/sub>, care se coreleaz\u0103 cu poten\u0163ialul proliferativ, iar acesta permite discriminarea a dou\u0103 subgrupuri de pacien\u0163i cu evolu\u0163ie clinic\u0103 diferit\u010311<\/sup>.<\/p>\n

Konoplev et al.<\/em> au ar\u0103tat \u00een studiul lor, \u00een care au determinat TK prin metoda de chemiluminiscen\u0163\u0103, c\u0103 un nivel seric crescut al TK prezice o supravie\u0163uire global\u0103 sc\u0103zut\u0103 \u015fi se coreleaz\u0103 cu lipsa muta\u0163iilor genei IgV\u0417<\/sub>, expresia CD38 \u015fi ZAP-70, nivelul \u03b22<\/sub>-microglobulinei serice \u015fi dezvoltarea \u00een continuare a sindromului Richter, acelea\u015fi aspecte fiind prezente \u015fi la un subset de pacien\u0163i trata\u0163i cu regimuri terapeutice bazate pe fludarabin\u01036<\/sup>.<\/p>\n

\u25aa In limfoame<\/span> TK a fost studiat\u0103 \u00een special \u00eentre 1980 \u015fi 1990, iar studiile efectuate au ar\u0103tat c\u0103 aceasta este crescut\u0103 \u00een special \u00een formele agresive19<\/sup>.<\/p>\n

Masaki et al.<\/em> au studiat pacien\u0163i cu limfom f\u0103r\u0103 limfadenopatie superficial\u0103. \u00cen aceste cazuri estimarea cre\u015fterii tumorale, respectiv a num\u0103rului de celule tumorale, se face cu ajutorul unor parametri clinici cum ar fi sIL2R, deoxitimidin kinaza (dTK), \u03b22<\/sub>MG \u015fi LDH. Concentra\u0163iile serice ale sIL2R au fost mai mari \u00een stadiul IV dec\u00e2t \u00een stadiile I, II \u015fi III, concentra\u0163iile serice ale dTK au fost mai mari \u00een stadiul IV dec\u00e2t \u00een stadiile II \u015fi III, iar concentra\u0163iile serice ale \u03b22<\/sub>MG au fost mai mari in stadiul IV dec\u00e2t \u00een stadiul I. Concentra\u0163iile LDH nu s-au corelat cu stadiul tumoral. Niveluri extrem de mari ale sIL2R \u015fi dTK pot fi observate la unii pacien\u0163i cu limfoame care secret\u0103 citokine \u015fi mediatori chimici atunci c\u00e2nd survine inflama\u0163ia secundar\u010319<\/sup>.<\/p>\n

Wakao et al. <\/em>au ar\u0103tat c\u0103 TK seric\u0103 \u015fi receptorul solubil pentru IL-2 (sIL2R) sunt markeri sensibili \u015fi intercorela\u0163i pentru recuren\u0163a \u00een limfomul malign, precum \u015fi mai buni predictori ai rec\u0103derii dec\u00e2t LDH-ul \u015fi IPI (International Prognostic Index)21<\/sup>.<\/p>\n

\u00cen studiul lor, Poley et al.<\/em> au ar\u0103tat c\u0103 \u00een gamapatiile monoclonale<\/span> nivelele serice ale TK sunt mai mici \u00een gamapatiile monoclonale cu semnifica\u0163ie nedeterminat\u0103 (MGUS) dac\u00e2t \u00een mielomul multiplu (MM), iar pacien\u0163ii cu MM stadiul I Durie-Salmon au nivele ale TK semnificativ mai mici dec\u00e2t cei cu stadii mai avansate. A existat o corela\u0163ie \u00eentre nivelul TK \u015fi indexul de marcare al plasmocitelor. De asemenea nivelurile TK variaz\u0103 \u00een func\u0163ie de cursul bolii \u015fi r\u0103spunsul la tratament, sc\u0103z\u00e2nd \u00een remisiune \u015fi cresc\u00e2nd \u00een rec\u0103dere. TK s-a dovedit a fi un puternic indicator prognostic, dup\u0103 2 ani 83% din pacien\u0163ii cu nivele pretratament ale TK <10 U\/L fiind \u00een via\u0163\u0103, fa\u0163\u0103 de 47% din cei cu nivele ale TK \u226510 U\/L. \u00cen alte limfoame non-Hodgkin pacien\u0163ii cu nivelul TK >10 U\/L au avut o urm\u0103rire median\u0103 de numai 7 luni, \u00een timp ce cei cu nivele mai mici nici nu au atins timpul de supravie\u0163uire median. Astfel determinarea TK poate ajuta \u00een monitorizarea cursului clinic al limfoamelor non-Hodgkin pe durata tratamentului \u015fi poate prezice prognosticul limfoamelor15<\/sup>.<\/p>\n

Proch\u00e1zka et al.<\/em> au studiat semnifica\u0163ia prognostic\u0103 a nivelurilor serice de TK1 la 170 pacien\u0163i \u00eenrola\u0163i prospectiv cu limfom folicular netratat. Nivelul TK1 la momentul ini\u0163ierii tratamentului s-a corelat cu stadiul clinic,\u00a0 scorul FLIPI (Follicular Lymphoma International Prognostic Index), nivelurile \u03b22<\/sub>MG \u015fi LDH \u015fi simptomele B de boal\u0103. Nu s-a g\u0103sit nici o corela\u0163ie cu gradul de limfom folicular \u015fi cu indexul proliferativ Ki-67. Nivelele TK1 \u226515 U\/L au fost identificate ca factor prognostic pentru supravie\u0163uirea global\u0103 \u015fi supravie\u0163uirea f\u0103r\u0103 progresie independent de variabilele scorului FLIPI16<\/sup>.<\/p>\n

\u00centr-un alt studiu, Suzuki et al.<\/em> au studiat 55 pacien\u0163i nou diagnostica\u0163i cu limfom cu celul\u0103 T periferic\u0103 (PTCL) \u015fi care au fost trata\u0163i cu CHOP. La pacien\u0163ii cu niveluri ale TK crescute supravie\u0163uirea global\u0103 a fost semnificativ mai mic\u0103, iar rata de r\u0103spuns global\u0103 a fost semnificativ sc\u0103zut\u010317<\/sup>.<\/p>\n

\u25aa Rolul TK a fost de asemenea studiat \u00een sindroamele mielodisplazice<\/span> (MDS). Aul et al.<\/em> au determinat nivelul TK serice la 146 pacien\u0163i cu MDS primare. 79% din pacien\u0163i au prezentat niveluri crescute la diagnostic, cei cu stadii mai avansate de boal\u0103 (RAEB, CMML, RAEB\/T) prezent\u00e2nd niveluri mai mari \u00een compara\u0163ie cu cei \u00een stadii precoce (RA \u015fi RARS). Totu\u015fi nivelurile TK nu s-au corelat cu procentul de bla\u015fti medulari. Activitatea TK la diagnostic a furnizat informa\u0163ii prognostice, supravie\u0163uirea la 2 \u015fi 5 ani fiind mai mare la pacien\u0163ii cu nivelul TK <10 U\/\u03bcL. Totu\u015fi nivelurile TK la diagnostic nu au fost utile \u00een predic\u0163ia transform\u0103rii \u00een leucemie acut\u0103 mieloid\u0103. Lu\u00e2nd \u00een considerare lipsa corel\u0103rii cu bla\u015ftii medulari, autorii au concluzionat c\u0103 cre\u015fterea nivelurilor TK \u00een MDS este atributabil\u0103 \u00een primul r\u00e2nd distruc\u0163iei intramedulare a precursorilor hematopoietici, similar hematopoiezei ineficiente din deficitul de vitamin\u0103 B12 asociat\u0103 cu niveluri crescute ale TK \u015fi LDH. TK este un parametru prognostic care poate fi folosit pentru predic\u0163ia supravie\u0163uirii, totu\u015fi valoarea predictiv\u0103 a TK nu este superioar\u0103 LDH1<\/sup>.<\/p>\n

\u00centr-un alt studiu, Musto et al.<\/em> au monitorizat nivelurile TK serice la 90 pacien\u0163i cu MDS. Nici o corela\u0163ie nu a fost g\u0103sit\u0103 \u00eentre nivelurile ini\u0163iale de TK \u015fi al\u0163i parametri clinici sau de laborator. \u00cen urma analizei statistice a fost stabilit un cut-off de 38 U\/\u03bcL, pacien\u0163ii cu valori ale TK >38 U\/\u03bcL prezent\u00e2nd o supravie\u0163uire semnificativ mai scurt\u0103 dec\u00e2t cei cu valori <38 U\/\u03bcL (8,2 versus 37,4 luni). Leucemia acut\u0103 mieloid\u0103 (AML) a ap\u0103rut la 81% din cei cu TK >38 U\/\u03bcL, fa\u0163\u0103 de 13% din cei cu niveluri mai mici la diagnostic, independent de subtipul FAB. De asemenea nivelurile TK crescute au fost utile pentru predic\u0163ia evolu\u0163iei \u00een AML \u00een cursul evolu\u0163iei bolii la pacien\u0163ii cu valori ini\u0163iale normale. Astfel autorii au concluzionat c\u0103 TK este un important factor prognostic \u00een MDS care se coreleaz\u0103 puternic cu dezvoltarea AML19<\/sup>.<\/p>\n

\u25aa Rolul TK a fost studiat \u015fi \u00een leucemiile acute<\/span>. Votava et al.<\/em> au m\u0103surat TK la 38 copii cu leucemie acut\u0103 (34 limfoblastice, 4 mieloblastice), iar rezultatele au ar\u0103tat niveluri foarte crescute la diagnostic (valoarea median\u0103 = 403 U\/L, normal <8 U\/L), \u00een timp ce \u00een remisiune valorile au fost mult mai sc\u0103zute (valoarea median\u0103 = 31 U\/L), iar \u00een rec\u0103dere au crescut considerabil (valoarea median\u0103 = 324 U\/L). Studiul a ar\u0103tat c\u0103 cre\u015fterea nivelurilor TK serice \u00een timpul perioadei de urm\u0103rire a fost un marker de ajutor \u00een recunoa\u015fterea \u00eentr-un stadiu precoce a rec\u0103derii, \u00een unele cazuri cu 1 lun\u0103 \u00eenaintea apari\u0163iei semnelor clinice. Sensibilitatea \u00een acest caz a fost de 87%. Astfel nivelurile serice ale TK par a fi un bun parametru \u00een perioada de urm\u0103rire datorit\u0103 sensibilit\u0103\u0163ii acceptabile, costului sc\u0103zut \u015fi elimin\u0103rii necesit\u0103\u0163ii screening-ului m\u0103duvei osoase. Totu\u015fi \u00een acest studiu nivelurile TK la diagnostic nu s-au corelat cu prognosticul20<\/sup>.<\/p>\n

O`Neill et al.<\/em> au m\u0103surat nivelul TK1 la pacien\u0163i cu ALL \u015fi AML \u015fi la un grup de pacien\u0163i f\u0103r\u0103 cancer prin 2 metode, radioenzimatic\u0103 \u015fi imunoenzimatic\u0103, cele dou\u0103 metode prezent\u00e2nd o corela\u0163ie putenic\u0103 \u00eentre m\u0103sur\u0103tori. Compararea valorilor medii ale TK1 la pacien\u0163ii cu ALL \u015fi la indivizii s\u0103n\u0103to\u015fi a ar\u0103tat diferen\u0163e semnificative statistic \u00eentre cele 2 grupuri, ceea ce confirm\u0103 m\u0103surarea nivelului TK1 serice ca un instrument diagnostic. De asemenea rezultatele ob\u0163inute au ar\u0103tat c\u0103 activitatea TK1 serice este un bun indicator al r\u0103spunsului la tratament \u015fi al stadiului bolii, nivelurile TK1 sc\u0103z\u00e2nd semnificativ la fiecare pacient care a r\u0103spuns la tratament \u015fi a intrat \u00een remisiune \u015fi cresc\u00e2nd la fiecare pacient care a rec\u0103zut14<\/sup>.<\/p>\n

Exist\u0103 pu\u0163ine date \u00een privin\u0163a rolului TK \u00een tumorile solide<\/span><\/strong>, majoritatea provenind din anii 1994-1998.<\/p>\n

\u25aa Cancerul de s\u00e2n<\/span> este cea mai comun\u0103 form\u0103 de cancer \u015fi a doua cauz\u0103 de deces prin cancer la femeile din civiliza\u0163ia vestic\u0103. \u00cen ciuda progreselor ob\u0163inute \u00een detec\u0163ia precoce \u015fi \u00een \u00een\u0163elegerea bazelor moleculare ale biologiei cancerului da s\u00e2n, 30% din pacientele \u00een stadiu precoce prezint\u0103 boal\u0103 recurent\u0103. Posibilitatea de a avea markeri prognostici \u015fi\/sau predictivi puternici este de cea mai mare importan\u0163\u0103 pentru clinicieni \u00een vederea identific\u0103rii pacientelor cu riscul cel mai mare de rec\u0103dere \u015fi selectarea tratamentului cel mai potrivit pentru fiecare pacient\u0103 \u00een parte. Un factor prognostic reprezint\u0103 o caracteristic\u0103 clinic\u0103 sau biologic\u0103 m\u0103surabil\u0103 asociat\u0103 cu perioada de supravie\u0163uire f\u0103r\u0103 boal\u0103 \u015fi supravie\u0163uirea global\u0103 independent de tratament, iar un factor predictiv reprezint\u0103 o caracteristic\u0103 m\u0103surabil\u0103 asociat\u0103 cu r\u0103spunsul sau lipsa r\u0103spunsului la un tratament specific. Dup\u0103 determinarea stadiului, gradului histologic \u015fi a statusului receptorului hormonal, totu\u015fi tumora poate avea o evolu\u0163ie nea\u015fteptat\u0103 \u015fi prognosticul poate varia. O serie de factori prognostici \u015fi predictivi au fost studia\u0163i \u00een scopul explic\u0103rii acestui fenomen, cum ar fi: expresia proteinei \u015fi amplificarea genei Her-2\/neu, expresia altor membri ai familiei receptorului factorului de cre\u015ftere epitelial\u0103, frac\u0163ia fazei S, ploidia ADN, muta\u0163iile genei p53, ciclina E, disreglarea p27, prezen\u0163a celulelor tumorale \u00een circula\u0163ie \u015fi m\u0103duva osoas\u0103, invazia spa\u0163iului perineural \u015fi limfovascular3,19<\/sup>. \u00cen 2002 ASCO (American Society of Clinical Oncology) a discutat markerii prognostici relevan\u0163i pentru cancerul de s\u00e2n, iar recomand\u0103rile lor includ numai receptorul pentru estrogen \u015fi Her-2\/neu, dar nu \u015fi CEA, CA15-3 \u015fi p53 datorit\u0103 rezultatelor contradictorii. \u00cen plus, deoarece numai 25-30% din pacientele cu cancer de s\u00e2n sunt Her-2\/neu pozitive, utilitatea acestui marker poate fi limitat\u0103. Aceste date indic\u0103 necesitatea de indicatori prognostici mai sensibili \u015fi specifici4<\/sup>.<\/p>\n

Nivele crescute ale TK au fost raportate \u00een cancerul de s\u00e2n. Svobodova et al.<\/em> au ar\u0103tat c\u0103 valorile preoperatorii ale TK la un grup de 400 paciente cu cancer de s\u00e2n au fost semnificativ mai mari dec\u00e2t la persoanele s\u0103n\u0103toase, dar sensibilitatea TK a fost de 35% la o specificitate de 95%. De asemenea valorile din remisiune au diferit semnificativ de cele din prima progresie, iar valorile preoperatorii nu s-au corelat cu intervalul f\u0103r\u0103 boal\u0103, dar s-au corelat cu supravie\u0163uirea global\u0103. O descoperire semnificativ\u0103 a fost cre\u015fterea sensibilit\u0103\u0163ii TK la 3-6 luni \u00eenaintea progresiei, c\u00e2nd sensibilitatea TK a fost mai mare dec\u00e2t a CA15-3 \u015fi considerabil mai mare dec\u00e2t a CEA. Astfel testarea simultan\u0103 a CA15-3 \u015fi TK va cre\u015fte considerabil detectarea precoce a rec\u0103derii tumorale. Aceste rezultate sunt \u00een acord cu datele publicate \u015fi de al\u0163i autori (O`Neill et al.<\/em>, Robertson et al.<\/em>, Kausitz et al.<\/em>)18;19<\/sup>.<\/p>\n

Nisman et al.<\/em> au studiat asocierea activit\u0103\u0163ii TK serice cu parametrii clinico-patologici \u015fi prognosticul, \u00een termenii supravie\u0163uirii f\u0103r\u0103 recuren\u0163\u0103, la 161 paciente cu cancer de s\u00e2n. Nivelele TK serice au fost semnificativ mai mari la pacientele cu cancer de s\u00e2n dec\u00e2t la femeile s\u0103n\u0103toase \u015fi s-au asociat cu stadiul T avansat, grad mai \u00eenalt, prezen\u0163a necrozei tumorale, invaziei vasculare, lipsa expresiei receptorului pentru estrogen \u015fi a receptorului pentru progesteron. De asemenea niveluri mai mari ale TK au fost prezente la pacientele cu muta\u0163ii BRCA1\/2 fa\u0163\u0103 de cele f\u0103r\u0103 muta\u0163ii. \u00cen urma analizei multivariate activitatea TK a fost g\u0103sit\u0103 ca factor de prognostic independent pentru supravie\u0163uirea f\u0103r\u0103 recuren\u0163\u010312<\/sup>.<\/p>\n

He et al.<\/em> au m\u0103surat concentra\u0163ia TK la 120 paciente cu cancer de s\u00e2n cu risc sc\u0103zut la momentul interven\u0163iei chirurgicale \u015fi la 67 paciente la 21 zile \u015fi la 3 luni dup\u0103 opera\u0163ie. Concentra\u0163ia TK la 3 luni post-operator a fost mai mare la pacientele care au dezvoltat recuren\u0163\u0103 la distan\u0163\u0103 sau loco-regional\u0103. \u00cen schimb CA15-3 \u015fi activitatea TK nu au fost sensibile \u00een detec\u0163ia precoce post-operator a recuren\u0163elor. Informa\u0163iile ob\u0163inute ar putea fi folosite \u00een decizia asupra terapiei adjuvante4<\/sup>.<\/p>\n

\u25aa Kemik et al.<\/em> au m\u0103surat concentra\u0163iile serice ale TK la 72 pacien\u0163i cu adenocarcinom gastric<\/span>. Nivelele TK s-au asociat cu stadiul tumoral avansat, prezen\u0163a metastazelor, prezen\u0163a adenopatiilor \u015fi diferen\u0163ierea tumoral\u0103 slab\u0103, suger\u00e2nd o posibil\u0103 semnifica\u0163ie prognostic\u01035<\/sup>.<\/p>\n

\u25aa Nisman et al.<\/em> au m\u0103surat nivelul plasmatic al piruvat kinakei tip M2 (TuM2-PK) \u015fi activitatea TK preoperator la 116 pacien\u0163i cu carcinom renocelular<\/span> \u015fi au g\u0103sit niveluri semnificativ mai mari \u00een compara\u0163ie cu participan\u0163ii s\u0103n\u0103to\u015fi dar nu \u015fi fa\u0163\u0103 de cei cu tumori renale benigne. Nivelurile celor 2 markeri s-au corelat semnificativ cu stadiul T, dar numai TuM2-PK s-a corelat cu gradul tumorii, iar prezen\u0163a necrozei tumorale extensive (>50%) s-a asociat cu TuM2-PK crescut \u015fi TK1 sc\u0103zut. Ambii markeri s-au dovedit markeri predictivi independen\u0163i pentru recuren\u0163\u0103. Astfel m\u0103surarea acestor markeri \u00eenaintea interven\u0163iei chirurgicale poate fi util\u0103 pentru stratificarea pacien\u0163ilor \u00een grupe de risc pentru un posibil tratament adjuvant13<\/sup>.<\/p>\n

\u25aa Li HX et al.<\/em>, Li Z et al.<\/em>, Korkmaz et al.<\/em> au studiat activitatea TK serice \u00een cancerul pulmonar non-microcelular<\/span> ar\u0103t\u00e2nd c\u0103 nivelurile preoperatorii ale TK au fost semnificativ mai mari fa\u0163\u0103 de pacien\u0163ii s\u0103n\u0103to\u015fi, la pacien\u0163ii din grupul M0 corel\u00e2ndu-se cu m\u0103rimea tumorii \u015fi stadiul bolii, dar nu \u015fi la pacien\u0163ii din grupul M1. Nivelul TK serice s-a dovedit un factor prognostic pentru monitorizarea r\u0103spunsului la chirurgie, iar la pacien\u0163ii cu cancer metastatic a reprezentat un factor prognostic independent pentru supravie\u0163uirea f\u0103r\u0103 progresie \u015fi supravie\u0163uirea global\u01037;9;10<\/sup>.<\/p>\n

Recomand\u0103ri pentru determinarea timidin <\/em><\/strong>kinazei<\/strong> \u2013 util\u0103 ca marker prognostic \u015fi \u00een monitorizarea leucemiei limfatice cronice, limfoamelor non-Hodgkin, leucemiilor; diferen\u0163ierea pacien\u0163ilor cu mielom multiplu de cei cu MGUS; posibil marker prognostic \u00een cancerul de s\u00e2n \u015fi alte tumori solide.<\/p>\n

Preg\u0103tire pacient <\/em><\/strong>- <\/em>\u00e0 jeun (pe nem\u00e2ncate)8<\/sup>.<\/p>\n

Specimen recoltat <\/em><\/strong>- <\/em>\u0432\u0435\u043d\u043e\u0437\u043d\u0430\u044f \u043a\u0440\u043e\u0432\u044c8<\/sup>.<\/p>\n

Recipient de recoltare <\/em><\/strong>- <\/em>vacutainer f\u0103r\u0103 anticoagulant, cu\/f\u0103r\u0103 gel separator8<\/sup>.<\/p>\n

Prelucrare necesar\u0103 dup\u0103 recoltare <\/em><\/strong>- <\/em>se separ\u0103 serul prin centrifugare; serul se p\u0103streaz\u0103 la -20\u00b0C8<\/sup>.<\/p>\n

Volum prob\u0103<\/em><\/strong> \u2013 1 mL ser8<\/sup>.<\/p>\n

Cauze de respingere<\/em><\/strong> a probei <\/em><\/strong>\u2013 specimen intens hemolizat, lipemic sau care con\u0163ine particule suspendate8<\/sup>.<\/p>\n

Stabilitate prob\u0103 <\/em><\/strong>- <\/em>serul separat este stabil 12 luni la -20\u00b0C8<\/sup>.<\/p>\n

Metod\u0103 <\/em><\/strong>- imunochimic\u0103 cu detec\u0163ie prin chemiluminiscen\u0163\u0103 (CLIA)<\/span>. Acesta este un test indirect \u00een 2 timpi pentru determinarea cantitativ\u0103 a TK. Ini\u0163ial are loc o reac\u0163ie enzimatic\u0103 \u00een care TK din prob\u0103 transform\u0103 AZT \u00een AZTMP, iar AZTMP este determinat cantitativ imunologic prin utilizarea de anticorpi anti-AZTMP8<\/sup>.<\/p>\n

Valori de referin\u0163\u0103 <\/em><\/strong>- <\/em>2 \u2013 7,5 U\/L.<\/p>\n

Sensibilitate analitic\u0103: <\/em><0,5 U\/L.<\/p>\n

Sensibilitate func\u0163ional\u0103: <\/em><5 U\/L8<\/sup>.<\/p>\n

Interpretarea rezultatelor: <\/em><\/strong>rezultatele vor fi coroborate cu alte date clinice \u015fi de laborator.<\/p>\n

Interpretarea acestui marker trebuie f\u0103cut\u0103 numai \u00een asociere cu evaluarea statusului clinic deoarece trebuie excluse alte cauze nespecifice de niveluri serice crescute: infec\u0163ii virale, \u00een special herpes simplex \u015fi zoster, boli autoimune, boli granulomatoase benigne (sarciodoz\u0103, hepatita cronic\u0103) \u015fi, \u00een mod particular, anemia pernicioas\u010318;19<\/sup>.<\/p>\n

O limitare a m\u0103sur\u0103rii activit\u0103\u0163ii TK1 este varia\u0163ia substan\u0163ial\u0103 a valorilor \u00eentre pacien\u0163i. Astfel modific\u0103ri \u00een activitatea TK1 serice sunt utile ca marker prognostic numai comparate cu probele anterioare ale pacientului, un nivel de baz\u0103 trebuind s\u0103 fie stabilit pentru fiecare pacient14<\/sup>.<\/p>\n

\u0411\u0438\u0431\u043b\u0438\u043e\u0433\u0440\u0430\u0444\u0438\u044f<\/span><\/strong><\/p>\n

\u00a01. Aul C, Gattermann N, Germing U, Winkelmann M, Heyll A, Runde V, Schneider W. Serum deoxithymidine kinase in myelodysplastic syndromes. In Cancer.<\/em> 1994; 73<\/strong>(2), 322-7.<\/span><\/div>\n
2. Di Raimondo F, Giustolisi R, Lerner S, Cacciola E, O`Brian S, Kantarjian H, Keating M I. Retrospective study of the role of serum thymidine kinase level in CLL patients with active disease treated with fludarabine. In Annals of Oncology <\/em>(2001) 12<\/strong>(5):621-625.<\/span><\/div>\n
3. Gonzales-Angulo AM, Morales-Vasquez F, Hortobaqyi GN. Overview of resistance to systemic therapy in patients with breast cancer. In Adv Exp Med Biol.<\/em> (2007), 608<\/strong>: 1-22.<\/span><\/div>\n
4. He Q, Fornander T, Johansson H, Johansson U, Hu GZ, Rutqvist LE, Skog S. Thymidine Kinase 1 in Serum Predicts Increased Risk of Distant or Loco-regional Recurrence Following Surgery in Patients with Early Breast Cancer. In ANTICANCER RESEARCH 26<\/strong><\/em>: 4753-4760 (2006).<\/span><\/div>\n
5. Kemik O, Kemik AS, Purisa S, Tuzun S. Serum thymidine kinase is associated with gastric adenocarcinoma. In Bratisl Lek Listy.<\/em> 2011; 112<\/strong>(9): 510-511.<\/span><\/div>\n
\u00a06. Konoplev S N, Fritsche H, O`Brian S, Wierda W, Keating M J, Gornet T, St Romain S, Wang X, Inamdar K, Johnson M, Medeiros L J, Bueso-Ramos C E. High Serum Thymidine Kinase 1 Level Predicts Poorer Survival in Patients with Chronic Lymphocytic Leukemia. In Am J Clin Pathol<\/em> (2010) 134<\/strong>, 472-477.<\/span><\/div>\n
7. Korkmaz T, Seber S, Basaran P, Yumuk PF, Dane F, Okutur K, Kanitez M, Kocar M, Telli F, Demir G, Turhal NS. S Prognostic significance of serum thymidine kinase activity (TK1) level in patients with metastatic non-small cell lung cancer (NSCLC). In J Clin Oncol\u00a0 <\/em>29:<\/em> 2011 (suppl; abstr e18010).<\/span><\/div>\n
8. Laborator Synevo. Referin\u0163ele specifice tehnologiei de lucru utilizate 2012. Ref Type: Catalog.\u00a0\u00a0\u00a0\u00a0<\/span><\/div>\n
9. Li HX, Lei DS, Wang XQ, Skog S, He Q. Serum thymidine kinase 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer. In Oncol Rep.<\/em> 2005 Jan; 13<\/strong>(1): 145-9.<\/span><\/div>\n
10. Li Z, Wang Y, He J, Ma J, Zhao L, Chen H, Li N, Zhou J, He E, Skog S. Serological thymidine kinase 1 is a prognostic factor in oesophageal, cardial and lung carcinomas. In Eur J Cancer Prev.<\/em> 2010 Jul; 19<\/strong>(4): 313-8.<\/span><\/div>\n
11.\u00a0\u00a0 Magnac C, Porcher R, Davi F, Nataf J, Payelle-Brogard B, Tang R P, Oppezzo P, L\u00e9vy V, Dighiero G, Ajchenbaum-Cymbalista F. Predictive value<\/span> of serum thymidine kinase level for Ig-V mutational status in B-CLL. In Leukemia<\/em> (2003) 17<\/strong>, 133-137.<\/span><\/div>\n
12.\u00a0\u00a0 Nisman B, Allweis T, Kaduri L, Maly B, Gronowitz S, Hamburger T, Peretz T. Serum thymidine kinase 1 activity in breast\u00a0cancer. In Cancer Biomark.<\/em> 2010; 7<\/strong>(2): 65-72.<\/span><\/div>\n
13.\u00a0\u00a0 Nisman B, Yutkin V, Nechushtan H, Gofrit ON, Peretz T, Gronowitz S, Pode D. Circulating Tumor M2 Pyruvate\u00a0Kinaseand Thymidine Kinase 1 Are Potential Predictors for Disease Recurrence in Renal Cell Carcinoma after\u00a0<\/span>Nephrectomy. In Urology.<\/em> 2010 Aug; 76<\/strong>(2): 513.e1-513.e6.<\/span><\/div>\n
14.\u00a0\u00a0 O`Neill K L, Zhang F, Li H, Fuja D G, Murray B K. Thymidine kinase 1 \u2013 A prognostic and diagnostic indicator in ALL and\u00a0AML patients. In Leukemia.<\/em> (2007) 21<\/strong>, 560-563.<\/span><\/div>\n
15. \u00a0\u00a0Poley S, Stieber P, N\u00fcssler V, Pahl H, Fateh-Moghadam A. Serum Thymidine Kinase in non-Hodgkin lymphomas with\u00a0special regard to multiple myeloma. In Oncol Rep.<\/em> 2005 Oct; 14<\/strong>(4), 1013-9.<\/span><\/div>\n
16. \u00a0\u00a0Proch\u00e1zka V, Faber E, Raida L, Langov\u00e1 K, Indr\u00e1k K, Papaj\u00edk T. High baseline serum thymidine kinase 1 level predict\u00a0unfavorable outcome in patients with follicular lymphoma. In Leuk Lymphoma<\/em>. 2011 oct. 31 [Epub ahead of print]<\/span><\/div>\n
17. \u00a0\u00a0Suzuki K, Terui Y, Nakano K, Nara E, Nasu K, Ueda K, Nishimura N, Mishima Y, Sakajiri S, Yokoyama M, Takahashi S,\u00a0Hatake K. High Thymidine kinase activity is a strong predictive factor for poor prognosis in PTCLs treated by CHOP.\u00a0In Nucleosides Nucleotides Nucleic Acids.<\/em> 2010 Jun; 29<\/strong>(4-6), 352-8.<\/span><\/div>\n
18.\u00a0\u00a0 Svobodova S., Topolcan O, Holubec L, Treska V, Sutnar A, Rupert K, Kormunda S, Rousarova M, Finek J. Prognostic\u00a0Importance of Thymidine Kinase in Colorectal and Breast Cancers. In ANTICANCER RESEARCH 27<\/strong><\/em>: 1907-1910\u00a0(2007).<\/span><\/div>\n
19. \u00a0\u00a0 Topolcan O, Holubec Jr L. The role of thymidine kinase in cancer diseases. In Expert Opin. Med. Diagn.,<\/em> (2008)\u00a02<\/strong>(2):129-141.<\/span><\/div>\n
20. \u00a0\u00a0Votava T, Topolcan O, Holubek L Jr, Cerna Z, Sasek L, Finek J, Kormunda S. Changes of serum thymidine kinase in\u00a0children with acute leukemia. In Anticancer Res.<\/em> 2007 Jul-Aug; 27<\/strong>(4A), 1925-8.<\/span><\/div>\n
21. \u00a0\u00a0Wakao D, Murohashi I, Tominaga K, Yoshida K, Kishimoto K, Yagasaki F, Itoh Y, Ytoh K, Sakata T, Kawai N, Kayano\u00a0H, Suzuki T, Matsuda A, Hirashima K, Bessho M. Serum thymidine kinase and soluble interleukin-2 receptor predict\u00a0recurrence in malignant lymphoma. Vnitr Lek<\/em> (1994) 40<\/strong>(3), 157-62.<\/span><\/div>","protected":false},"excerpt":{"rendered":"

\u0422\u0438\u043c\u0438\u0434\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u0430 – \u0432\u043d\u0443\u0442\u0440\u0438\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u044b\u0439 \u0444\u0435\u0440\u043c\u0435\u043d\u0442, \u043a\u0430\u0442\u0430\u043b\u0438\u0437\u0438\u0440\u0443\u044e\u0449\u0438\u0439 \u043f\u0440\u0435\u0432\u0440\u0430\u0449\u0435\u043d\u0438\u0435 \u0442\u0438\u043c\u0438\u0434\u0438\u043d\u0430 \u0432 \u0442\u0438\u043c\u0438\u0434\u0438\u043d \u043c\u043e\u043d\u043e\u0444\u043e\u0441\u0444\u0430\u0442 (\u0422\u041c\u0424) \u0432 \u043f\u0440\u0438\u0441\u0443\u0442\u0441\u0442\u0432\u0438\u0438 \u0430\u0434\u0435\u043d\u043e\u0437\u0438\u043d\u0442\u0440\u0438\u0444\u043e\u0441\u0444\u0430\u0442\u0430 (\u0410\u0422\u0424). \u0412 \u0445\u043e\u0434\u0435 \u043d\u0435\u0441\u043a\u043e\u043b\u044c\u043a\u0438\u0445 \u0441\u0442\u0430\u0434\u0438\u0439 \u0422\u041c\u0424 \u043f\u0440\u0435\u0432\u0440\u0430\u0449\u0430\u0435\u0442\u0441\u044f \u0432 \u0442\u0438\u043c\u0438\u0434\u0438\u043d \u0442\u0440\u0438\u0444\u043e\u0441\u0444\u0430\u0442 \u0438 \u0432\u043a\u043b\u044e\u0447\u0430\u0435\u0442\u0441\u044f \u0432 \u0441\u043e\u0441\u0442\u0430\u0432 \u0434\u0435\u0437\u043e\u043a\u0441\u0438\u0440\u0438\u0431\u043e\u043d\u0443\u043a\u043b\u0435\u0438\u043d\u043e\u0432\u043e\u0439 \u043a\u0438\u0441\u043b\u043e\u0442\u044b (\u0414\u041d\u041a). \u0410 \u0442\u0430\u043a \u043a\u0430\u043a \u0442\u0438\u043c\u0438\u0434\u0438\u043d \u043c\u043e\u0436\u0435\u0442 \u0432\u043a\u043b\u044e\u0447\u0430\u0442\u044c\u0441\u044f \u0432 \u0414\u041d\u041a \u0442\u043e\u043b\u044c\u043a\u043e \u0432 \u0444\u043e\u0441\u0444\u043e\u0440\u0438\u043b\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u043e\u0439 \u0444\u043e\u0440\u043c\u0435, \u0422\u041a \u0438\u0433\u0440\u0430\u0435\u0442 \u043a\u043b\u044e\u0447\u0435\u0432\u0443\u044e \u0440\u043e\u043b\u044c \u0432 \u043f\u0440\u043e\u0446\u0435\u0441\u0441\u0435 \u043c\u0435\u0442\u0430\u0431\u043e\u043b\u0438\u0437\u043c\u0430 \u0442\u0438\u043c\u0438\u0434\u0438\u043d\u0430 \u0432 \u043a\u043b\u0435\u0442\u043a\u0435. \u0421\u0438\u043d\u0442\u0435\u0437 \u0422\u041c\u0424 \u0438\u0437 \u043c\u043e\u043d\u043e\u0444\u043e\u0441\u0444\u0430\u0442\u0430 \u0434\u0435\u0437\u043e\u043a\u0441\u0438\u0443\u0440\u0438\u0434\u0438\u043d\u0430 \u043e\u0431\u044b\u0447\u043d\u043e \u043a\u0430\u0442\u0430\u043b\u0438\u0437\u0438\u0440\u0443\u0435\u0442\u0441\u044f \u0442\u0438\u043c\u0438\u0434\u0438\u043b\u0430\u0442\u0441\u0438\u043d\u0442\u0435\u0442\u0430\u0437\u043e\u0439 \u0432 \u043f\u0440\u0438\u0441\u0443\u0442\u0441\u0442\u0432\u0438\u0438 \u0444\u043e\u043b\u0438\u0435\u0432\u043e\u0439 \u043a\u0438\u0441\u043b\u043e\u0442\u044b \u0438 \u0432\u0438\u0442\u0430\u043c\u0438\u043d\u0430 \u041212. \u0422\u0438\u043c\u0438\u0434\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u0430, \u0432 \u043e\u0442\u043b\u0438\u0447\u0438\u0435 \u043e\u0442 \u0442\u0438\u043c\u0438\u0434\u0438\u043b\u0430\u0442\u0441\u0438\u043d\u0442\u0435\u0442\u0430\u0437\u044b, \u0438\u0441\u043f\u043e\u043b\u044c\u0437\u0443\u0435\u0442 \u0432 \u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435 \u0441\u0443\u0431\u0441\u0442\u0440\u0430\u0442\u0430 \u043b\u0438\u0431\u043e \u044d\u043a\u0437\u043e\u0433\u0435\u043d\u043d\u044b\u0439 \u0442\u0438\u043c\u0438\u0434\u0438\u043d, \u043f\u043e\u0441\u0442\u0443\u043f\u0430\u044e\u0449\u0438\u0439 \u0441 \u043f\u0438\u0449\u0435\u0439, \u043b\u0438\u0431\u043e \u044d\u043d\u0434\u043e\u0433\u0435\u043d\u043d\u044b\u0439 \u0442\u0438\u043c\u0438\u0434\u0438\u043d, \u043e\u0431\u0440\u0430\u0437\u0443\u044e\u0449\u0438\u0439\u0441\u044f \u0432 \u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u0435 \u043c\u0435\u0442\u0430\u0431\u043e\u043b\u0438\u0447\u0435\u0441\u043a\u0438\u0445 \u043f\u0440\u043e\u0446\u0435\u0441\u0441\u043e\u0432. \u041f\u043e\u044d\u0442\u043e\u043c\u0443 \u0435\u0435 \u043d\u0430\u0437\u044b\u0432\u0430\u044e\u0442 \u00absalvage\u00bb \u044d\u043d\u0437\u0438\u043c\u043e\u043c — \u00ab\u0441\u043f\u0430\u0441\u0430\u0442\u0435\u043b\u044c\u043d\u044b\u043c\u00bb \u0438\u043b\u0438 \u00ab\u0443\u0442\u0438\u043b\u0438\u0437\u0438\u0440\u0443\u044e\u0449\u0438\u043c\u00bb \u0444\u0435\u0440\u043c\u0435\u043d\u0442\u043e\u043c.<\/p>\n

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\u041f\u043e\u0432\u044b\u0448\u0435\u043d\u043d\u044b\u0435\u00a0\u0443\u0440\u043e\u0432\u043d\u0438\u00a0\u0443\u00a0\u0431\u043e\u043b\u044c\u043d\u044b\u0445\u00a0\u0441\u043e\u00a0\u0437\u043b\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u044b\u043c\u0438\u00a0\u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0432\u044b\u043c\u0438\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u043c\u0438:<\/p>\n

    \n
  • \u0437\u043b\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u044b\u0435\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u00a0\u043a\u0440\u043e\u0432\u0438;<\/li>\n
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  • \u0440\u0430\u043a\u00a0\u044f\u0438\u0447\u043a\u0430;<\/li>\n
  • \u0440\u0430\u043a\u00a0\u043c\u043e\u0447\u0435\u0432\u043e\u0433\u043e\u00a0\u043f\u0443\u0437\u044b\u0440\u044f;<\/li>\n
  • \u043a\u0430\u0440\u0446\u0438\u043d\u043e\u043c\u0430\u0442\u043e\u0437\u00a0\u0441\u0435\u0440\u043e\u0437\u043d\u044b\u0445\u00a0\u043e\u0431\u043e\u043b\u043e\u0447\u0435\u043a;<\/li>\n
  • \u0440\u0430\u043a\u00a0\u043f\u0440\u043e\u0441\u0442\u0430\u0442\u044b.<\/li>\n<\/ul>\n

    \u041f\u043e\u0432\u044b\u0448\u0435\u043d\u043d\u044b\u0435\u00a0\u0443\u0440\u043e\u0432\u043d\u0438\u00a0\u043f\u0440\u0438\u00a0\u0434\u043e\u0431\u0440\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u044b\u0445\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u0445:<\/p>\n

      \n
    • \u0432\u0438\u0440\u0443\u0441\u043d\u0430\u044f\u00a0\u0438\u043d\u0444\u0435\u043a\u0446\u0438\u044f;<\/li>\n
    • \u043f\u0441\u043e\u0440\u0438\u0430\u0437;<\/li>\n
    • \u0442\u0443\u0431\u0435\u0440\u043a\u0443\u043b\u0435\u0437\u043d\u044b\u0439\u00a0\u043f\u043b\u0435\u0432\u0440\u0438\u0442;<\/li>\n
    • \u0441\u0430\u0440\u043a\u043e\u0438\u0434\u043e\u0437;<\/li>\n
    • \u0440\u0435\u0432\u043c\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u0435\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f;<\/li>\n
    • \u0432\u043e\u0441\u043f\u0430\u043b\u0438\u0442\u0435\u043b\u044c\u043d\u044b\u0435\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u00a0\u043b\u0435\u0433\u043a\u0438\u0445\u00a0\u0438\u00a0\u043f\u0438\u0449\u0435\u0432\u0430\u0440\u0438\u0442\u0435\u043b\u044c\u043d\u043e\u0433\u043e\u00a0\u0430\u043f\u043f\u0430\u0440\u0430\u0442\u0430;<\/li>\n
    • \u043f\u0435\u0440\u043d\u0438\u0446\u0438\u043e\u0437\u043d\u0430\u044f\u00a0\u0438\u00a0\u043c\u0435\u0433\u0430\u043b\u043e\u0431\u043b\u0430\u0441\u0442\u043d\u0430\u044f\u00a0\u0430\u043d\u0435\u043c\u0438\u044f;<\/li>\n
    • \u043a\u043e\u043b\u043b\u0430\u0433\u0435\u043d\u043e\u0437\u044b.<\/li>\n<\/ul>\n\n\n\n\n\n\n\n\n
      \u041f\u043e\u043a\u0430\u0437\u0430\u0442\u0435\u043b\u044c<\/b><\/td>\n\u0425\u0430\u0440\u0430\u043a\u0442\u0435\u0440\u0438\u0441\u0442\u0438\u043a\u0430<\/b><\/td>\n<\/tr>\n
      \u041c\u0430\u0442\u0435\u0440\u0438\u0430\u043b<\/b><\/td>\n\u0412\u0435\u043d\u043e\u0437\u043d\u0430\u044f\u00a0\u043a\u0440\u043e\u0432\u044c<\/td>\n<\/tr>\n
      \u041f\u0440\u0430\u0432\u0438\u043b\u0430\u00a0\u043f\u043e\u0434\u0433\u043e\u0442\u043e\u0432\u043a\u0438\u00a0\u043f\u0430\u0446\u0438\u0435\u043d\u0442\u0430<\/b><\/td>\n\u0421\u0442\u0430\u043d\u0434\u0430\u0440\u0442\u043d\u044b\u0435<\/td>\n<\/tr>\n
      \u0422\u0440\u0430\u043d\u0441\u043f\u043e\u0440\u0442\u043d\u0430\u044f\u00a0\u0441\u0440\u0435\u0434\u0430,\u00a0\u043f\u0440\u043e\u0431\u0438\u0440\u043a\u0430<\/b><\/td>\n\u0412\u0430\u043a\u0443\u0442\u0430\u0439\u043d\u0435\u0440\u00a0\u0441\/\u0431\u0435\u0437\u00a0\u0430\u043d\u0442\u0438\u043a\u043e\u0430\u0433\u0443\u043b\u044f\u043d\u0442\u0430\u00a0\u0441\/\u0431\u0435\u0437\u00a0\u0433\u0435\u043b\u0435\u0432\u043e\u0439\u00a0\u0444\u0430\u0437\u044b<\/td>\n<\/tr>\n
      \u041f\u0440\u0430\u0432\u0438\u043b\u0430\u00a0\u0438\u00a0\u0443\u0441\u043b\u043e\u0432\u0438\u044f\u00a0\u0442\u0440\u0430\u043d\u0441\u043f\u043e\u0440\u0442\u0438\u0440\u043e\u0432\u043a\u0438,\u00a0\u0441\u0442\u0430\u0431\u0438\u043b\u044c\u043d\u043e\u0441\u0442\u044c\u00a0\u043f\u0440\u043e\u0431\u044b<\/b><\/td>\n\u0421\u0442\u0430\u043d\u0434\u0430\u0440\u0442\u043d\u044b\u0435<\/td>\n<\/tr>\n
      \u0420\u0435\u0444\u0435\u0440\u0435\u043d\u0442\u043d\u044b\u0435\u00a0\u0437\u043d\u0430\u0447\u0435\u043d\u0438\u044f<\/b>,\u00a0U\/L<\/b><\/td>\n2,0-7,5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n
      \u041f\u043e\u043a\u0430\u0437\u0430\u043d\u0438\u044f\u00a0\u043a\u00a0\u043d\u0430\u0437\u043d\u0430\u0447\u0435\u043d\u0438\u044e<\/b><\/td>\n<\/tr>\n
      \u00b7\u00a0\u0414\u0438\u0430\u0433\u043d\u043e\u0441\u0442\u0438\u043a\u0430\u00a0\u0438\u00a0\u043d\u0430\u0431\u043b\u044e\u0434\u0435\u043d\u0438\u0435\u00a0\u0437\u0430\u00a0\u043f\u0440\u043e\u0446\u0435\u0441\u0441\u043e\u043c\u00a0\u0433\u0435\u043c\u043e\u0431\u043b\u0430\u0441\u0442\u043e\u0437\u0430;<\/p>\n

      \u00b7\u00a0\u0434\u0438\u0430\u0433\u043d\u043e\u0441\u0442\u0438\u043a\u0430\u00a0\u0438\u00a0\u043d\u0430\u0431\u043b\u044e\u0434\u0435\u043d\u0438\u0435\u00a0\u043b\u0438\u043c\u0444\u043e\u043c;<\/p>\n

      \u00b7\u00a0\u0434\u043e\u043f\u043e\u043b\u043d\u0438\u0442\u0435\u043b\u044c\u043d\u044b\u0439\u00a0\u043c\u0430\u0440\u043a\u0435\u0440\u00a0\u043f\u0440\u0438\u00a0\u0432\u0441\u0435\u0445\u00a0\u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0432\u044b\u0445\u00a0\u0434\u0438\u0430\u0433\u043d\u043e\u0437\u0430\u0445,\u00a0\u043f\u0440\u0438\u00a0\u043e\u0446\u0435\u043d\u043a\u0435\u00a0\u0430\u0433\u0440\u0435\u0441\u0441\u0438\u0432\u043d\u043e\u0441\u0442\u0438\u00a0\u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0432\u043e\u0433\u043e\u00a0\u043f\u0440\u043e\u0446\u0435\u0441\u0441\u0430<\/td>\n<\/tr>\n

      \u0418\u043d\u0442\u0435\u0440\u043f\u0440\u0435\u0442\u0430\u0446\u0438\u044f\u00a0\u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u043e\u0432<\/b><\/td>\n<\/tr>\n
      \u041f\u0440\u0438\u00a0\u043e\u0446\u0435\u043d\u043a\u0435\u00a0\u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u043e\u0432\u00a0\u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u044f\u00a0\u043e\u043d\u043a\u043e\u043c\u0430\u0440\u043a\u0435\u0440\u0430\u00a0\u043d\u0435\u043e\u0431\u0445\u043e\u0434\u0438\u043c\u043e\u00a0\u0443\u0447\u0438\u0442\u044b\u0432\u0430\u0442\u044c\u00a0\u0441\u043b\u0435\u0434\u0443\u044e\u0449\u0435\u0435:<\/p>\n

      \u00b7\u00a0\u043d\u0435\u043a\u043e\u0442\u043e\u0440\u044b\u0435\u00a0\u043d\u0435\u043e\u043d\u043a\u043e\u043b\u043e\u0433\u0438\u0447\u0435\u0441\u043a\u0438\u0435\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u00a0\u0441\u043e\u043f\u0440\u043e\u0432\u043e\u0436\u0434\u0430\u044e\u0442\u0441\u044f\u00a0\u043f\u043e\u0432\u044b\u0448\u0435\u043d\u0438\u0435\u043c\u00a0\u0443\u0440\u043e\u0432\u043d\u044f\u00a0\u043e\u043d\u043a\u043e\u043c\u0430\u0440\u043a\u0435\u0440\u0430.<\/p>\n

      \u041d\u0430\u043f\u0440\u0438\u043c\u0435\u0440,\u00a0\u0443\u0440\u043e\u0432\u0435\u043d\u044c\u00a0\u0442\u0438\u043c\u0438\u0434\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u044b\u00a0\u043f\u043e\u0432\u044b\u0448\u0430\u0435\u0442\u0441\u044f\u00a0\u0432\u00a010\u00a0\u0440\u0430\u0437\u00a0\u043f\u0440\u0438\u00a0\u0432\u0438\u0440\u0443\u0441\u043d\u044b\u0445\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u0445;<\/p>\n

      \u00b7\u00a0\u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0432\u044b\u0435\u00a0\u043c\u0430\u0440\u043a\u0435\u0440\u044b\u00a0\u043d\u0435\u00a0\u0438\u043c\u0435\u044e\u0442\u00a0\u0430\u0431\u0441\u043e\u043b\u044e\u0442\u043d\u043e\u0439\u00a0\u043e\u0440\u0433\u0430\u043d\u043e\u0441\u043f\u0435\u0446\u0438\u0444\u0438\u0447\u043d\u043e\u0441\u0442\u0438;<\/p>\n

      \u00b7\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u044f\u00a0\u043f\u0435\u0447\u0435\u043d\u0438\u00a0\u0438\u00a0\u043f\u043e\u0447\u0435\u043a,\u00a0\u0432\u043b\u0438\u044f\u044e\u0449\u0438\u0435\u00a0\u043d\u0430\u00a0\u043c\u0435\u0442\u0430\u0431\u043e\u043b\u0438\u0437\u043c\u00a0\u043e\u043d\u043a\u043e\u043c\u0430\u0440\u043a\u0435\u0440\u043e\u0432,\u00a0\u043c\u043e\u0433\u0443\u0442\u00a0\u0438\u0437\u043c\u0435\u043d\u044f\u0442\u044c\u00a0\u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u044b\u00a0\u0430\u043d\u0430\u043b\u0438\u0437\u0430;<\/p>\n

      \u00b7\u00a0\u0440\u0435\u0448\u0430\u044e\u0449\u0438\u043c\u00a0\u044f\u0432\u043b\u044f\u0435\u0442\u0441\u044f\u00a0\u043d\u0435\u00a0\u0430\u0431\u0441\u043e\u043b\u044e\u0442\u043d\u044b\u0439\u00a0\u0443\u0440\u043e\u0432\u0435\u043d\u044c\u00a0\u043c\u0430\u0440\u043a\u0435\u0440\u0430,\u00a0\u0430\u00a0\u0434\u0438\u043d\u0430\u043c\u0438\u043a\u0430\u00a0\u0435\u0433\u043e\u00a0\u0438\u0437\u043c\u0435\u043d\u0435\u043d\u0438\u0439;<\/p>\n

      \u00b7\u00a0\u043e\u0442\u0440\u0438\u0446\u0430\u0442\u0435\u043b\u044c\u043d\u044b\u0439\u00a0\u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u00a0\u043d\u0435\u00a0\u043e\u0437\u043d\u0430\u0447\u0430\u0435\u0442,\u00a0\u0447\u0442\u043e\u00a0\u0437\u0430\u0431\u043e\u043b\u0435\u0432\u0430\u043d\u0438\u0435\u00a0\u043e\u0442\u0441\u0443\u0442\u0441\u0442\u0432\u0443\u0435\u0442<\/td>\n<\/tr>\n<\/tbody>\n<\/table>","protected":false},"featured_media":0,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"product_brand":[],"product_cat":[923],"product_tag":[],"class_list":{"0":"post-10121","1":"product","2":"type-product","3":"status-publish","5":"product_cat-markeri-tumorali","7":"first","8":"instock","9":"sold-individually","10":"shipping-taxable","11":"purchasable","12":"product-type-simple"},"_links":{"self":[{"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/product\/10121","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/product"}],"about":[{"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/types\/product"}],"replies":[{"embeddable":true,"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/comments?post=10121"}],"wp:attachment":[{"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/media?parent=10121"}],"wp:term":[{"taxonomy":"product_brand","embeddable":true,"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/product_brand?post=10121"},{"taxonomy":"product_cat","embeddable":true,"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/product_cat?post=10121"},{"taxonomy":"product_tag","embeddable":true,"href":"https:\/\/old.synevo.md\/ru\/wp-json\/wp\/v2\/product_tag?post=10121"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}