Kanptotezina eta haren deribatuak minbiziaren aurkako borrokan: Topoisomerasa I inhibitzaileak

Abstract

ABSTRACT: Cancer has been identified as one of the leading causes of death worldwide, claiming almost 10 million lives by 2020, according to the WHO. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds that may behave as topoisomerase I inhibitors with antiproliferative effect has become an active field of research. Investigation related to topoisomerase I inhibitors in cancer therapy started with camptothecin (CPT). This compound was first selected as a good anticancer agent and then topoisomerase I was identified as its therapeutic target. CPT and its derivatives (irinotecan, topotecan and belotecan) are the only clinically approved inhibitors. Currently, their limitations are being addressed by means of the use of combination therapies with different drugs, drugs combined with antibodies, adoption of protocols to increase the bioavailability, such as administration of nanoparticles, emulsions, liposomes. Future studies should focus not only on developing other active molecules, but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.; Minbizia heriotza-eragile nagusienen artean azaltzen da mundu mailan; 2020an, esaterako, 10 milioi heriotza inguru eragin zituen, WHO (World Health Organization) erakundearen arabera. Minbiziaren aurkako tratamendu farmakologikoari dagokionez, agente kimioterapiko eraginkorrenen artean balidatuta dago topoisomerasa I (TOP1, DNAren metabolismoan era zuzenean parte hartzen duen entzima) aparteko itu terapeutiko gisa. Era honetan, molekula antiproliferatibo berrien garapenerako interes handiko ikerketa arloa bilakatu da TOP1 inhibitzeko gai diren konposatu kimiko berrien sintesia. Historiari begiratuz, kanptotezina (KPT) izan zen aurkitu zen lehen giza topoisomerasa I (TOP1)-en inhibitzailea, 70eko hamarkadan. Harrezkero, KPTren eratorri sintetiko seguruagoak garatu dira (irinotekan, topotekan eta belotekan besteak beste), gaur egun erabilera klinikorako onarpena jaso duten TOP1 inhibitzaile bakarrak, alegia. Hala eta guztiz ere, bigarren belaunaldiko KPTren eratorri sintetiko hauek eragozpen kimiko anitz erakusten dituzte, haien erabilera klinikoa erabat mugatzen dutenak. Gaur egungo erreferentziazko ikerketen norabidea da, molekula aktibo berrien sintesiaz gain, KPTren eratorrien eta bestelako hautagai terapeutiko potentzialen eraginkortasuna eta aktibitate biologikoa hobetzea, hala nola farmako konbinazio sinergikoak bilatuz eta konposatu kimikoen farmakozinetika modulatuz.