PROTEAZOMNI INHIBITORI–RACIONALA KLINIČKE PRIMENE U TRETMANU MULTIPLOG MIJELOMA
Sažetak
Proteazomni inhibitori (PI) predstavljaju klasu lekova koji vrše inhibiciju katalitičke himotripsin–nalikujuće proteolizne podjedinice proteazoma. Inhibicija ove specifične strukture dovoljna je da zaustavi aktivnost čitave ubikvitin-proteazom mašinerije. Komletan protok proteina kroz ćeliju regulisan je aktivnošću proteazoma koji vrše bazalnu i signalno aktiviranu proteolizu kao odgovor na razne ćelijske stimuluse. Blokadom rada proteazoma dolazi do proteinske hiperkoncentracije u ćeliji što rezultuje aktivaciji mehanizama ćelijske smrti, što i jeste cilj dejstva PI protiv kancerske ćelije. Multipli mijelom (MM) je drugi po učestalosti od hematoloških maligniteta. Okosnicu terapije ove bolesti čine triplet–kombinacije komponovane od dugodelujućeg kortikosteroida (deksametazon), imunomodulatornih lekova (IMID), kao što su talidomid, lenalidomid ili pomalidomid i PI. U reberzibilne PI spadaju: bortezomib i iksazomib, dok u ireverzibilne PI spadaju: karfilzomib, oprozomib i marizomib. Strategija lečenja podrazumeva primenu uvodne (indukcione) hemioterapije, nakon koje se primenjuje visokodozna hemioterapija potpomognuta autologom transplantacijom matičnih ćelija hematopoeze. Ovakav modalitet lečenja se primenjuje ukoliko je bolest senzitivna, kao mera konsolidacije i rezervisan je za mlađe bolesnike (≤65 godina). Stariji bolesnici se najčešće tretiraju medikamentno bez primene transplantacionih procedura. Pitanje primene terapije održavanja nakon postignute remisije i dalje ostaje stvar značajnih kontroverzi, iako ga mnogi centri primenjuju bez utemeljenja u naučnim činjenicama. Bezbedonosni profil PI relativno je podnošljiv sa akcentovanim neželjenim efektima tipa periferne neuropatije, gastrointestinalne i umerene hematološke toksičnosti. Ovaj rad će razmatrati, izdvojeno, kliničku farmakologiju PI.
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