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Preparatele Anticorpilor Monoclonali În Oncologie

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Preparatele Anticorpilor Monoclonali În Oncologie 224 Buletinul AȘM CZU: 616-006.3-097+615.277.3 PREPARATELE ANTICORPILOR MONOCLONALI ÎN ONCOLOGIE BACINSCHI N., CARACAȘ A., VASILACHE E., MIHALACHI-ANGHEL M., CHIANU M. Catedra de farmacologie și farmacologie clinică Universitatea de Stat de Medicină și Farmacie „Nicolae Testemițanu”, Chișinău, Republica Moldova Rezumat Introducere. Terapia anticanceroasă clasică (radioterapie, chirurgie și chimioterapie sistemică), deși a cunoscut o evoluție în ascensiune permanentă, prezintă mai multe dezavantaje ce limitează termenii efectuării acesteia și eficacitatea clinică. Anticorpii monoclonali, ca o clasă majoră de preparate pentru tratamentul maladiilor oncologice, prin proprietă- țile farmacologice constituie o strategie indiscutabilă a conduitei terapeutice. Scop. Analiza și sistematizarea preparatelor anticorpilor monoclonali utilizate în tratamentul patologiei oncologice. Materiale și metode. Au fost selectate și analizate articolele din baza de date PubMed după cuvintele-cheie „anticor- pi monoclonali”, „oncologie”, „antitumorale”. Rezultate. S-au selectat preparatele anticorpilor monoclonali disponibile pe piața farmaceutică. S-au evidențiat an- ticorpi monoclonali simpli sau neconjugați (participă nemijlocit în realizarea efectului terapeutic) și conjugați (efectul curativ este determinat de substanțele atașate la anticorp - particule radioactive, citostatice, toxine etc.). S-a constatat că anticorpii monoclonali simpli acționează prin: cuplarea cu antigenii exprimați pe celulele canceroase; inițierea mecanis- melor răspunsului imun natural al organismului care exercită efect citotoxic; interacțiunea cu antigenii ce asigură prolife- rarea sau creșterea tumorii. Mecanismele acțiunii citotoxice a anticorpilor monoclonali, cauzate de interacțiunea specifică cu receptorii antigenilor pe celulele tumorale, se pot reduce la: activarea componentelor complementului; inducerea citotoxicității anticorp-dependente; inducerea apoptozei; blocarea receptorilor și întreruperea lanțurilor de semnalizare intracelulară; inhibarea moleculelor biologic active pentru realizarea fenotipului tumoral; inducerea răspunsului idio- sau antiidiotipic; inhibarea creșterii tumorii prin diminuarea formării vaselor noi etc. Concluzii. Preparatele anticorpilor monoclonali prin mecanismele și acțiunea țintită, influența asupra verigilor sis- temului imun și ciclului celular, utilizarea biotehnologiilor contemporane se consideră agenți antitumorali promițători în medicina personalizată a cancerului. Cuvinte-cheie: anticorpi monoclonali, activitate antitumorală, maladii oncologice, imunoglobuline, antigeni. Summary: Monoclonal antibody drugs in oncology. Introduction. Classical anticancer therapy (radiotherapy, surgery and systemic chemotherapy), although it has evolved in permanent ascension, has several disadvantages that limit the terms of its use and clinical efficacy. Monoclonal antibodies, as a major class of drugs for the treatment of oncological diseases, through their pharmacological properties represents an unquestionable strategy of therapeutic approach. Aim. Analysis and systematization of monoclonal antibody drugs used in the treatment of oncological diseases. Materials and methods. Were selected and analyzed the articles from the PubMed database according to the key- words „monoclonal antibodies”, „oncology”, „antitumor”. Results. Were selected the monoclonal antibody drugs available on the pharmaceutical market. Simple or unconju- gated monoclonal antibodies (directly involved in achieving the therapeutic effect) and conjugated (the therapeutic effect is determined by the substances attached to the antibody - radioactive particles, cytostatics, toxins, etc.) were highlighted. It has been found that simple monoclonal antibodies act by: coupling with antigens on cancer cells; initiating the mech- anisms of the body’s natural immune response that exerts a cytotoxic effect; interaction with antigens that assures tumor proliferation or tumor growth. The mechanisms of cytotoxic action of monoclonal antibodies, caused by the specific interaction with antigen receptors on tumor cells, can be reduced to: activation of complement components; induction of antibody-dependent cytotoxicity; induction of apoptosis; blocking receptors and disrupting intracellular signaling chains; inhibition of biologically active molecules to achieve the tumor phenotype; induction of the idio- or anti-idiotypic re- sponse; inhibiting tumor growth by reducing the formation of new vessels, etc. Conclusions. Monoclonal antibodies drugs through the mechanisms and targets of action, the influence on the links of the immune system and the cell cycle, the use of contemporary biotechnologies are considered promising antitumor agents in personalized cancer therapy. Key-words: monoclonal antibodies, antitumor activity, oncological diseases, immunoglobulins, antigens. Резюме: Препараты моноклональных антител в онкологии. Введение. Классическая противоопухолевая терапия (лучевая терапия, хирургия и системная химиотерапия), несмотря на постоянное развитие, имеет ряд недостатков, ограничивающих продолжительность проведения и Științe Medicale 225 клиническую эффективность. Моноклональные антитела, как основной класс препаратов для лечения онкологи- ческих заболеваний, благодаря своим фармакологическим свойствам представляют бесспорную стратегию тера- певтического воздействия. Цель. Анализ и систематизация препаратов моноклональных антител, используемых при лечении онкологи- ческой патологии. Материалы и методы. Из базы данных PubMed были выбраны и проанализированы статьи по ключевым словам «моноклональные антитела», «онкология», «противоопухолевые». Результаты. Были систематизированы препараты моноклональных антител, доступные на фармацевтическом рынке. Различают простые или неконъюгированные (непосредственно участвующие в достижении терапевтическо- го эффекта) и конъюгированные моноклональные антитела (лечебный эффект определяется веществами, присоеди- ненными к антителу - радиоактивными частицами, цитостатиками, токсинами и т. д.). Показано, что простые мо- ноклональные антитела реализуют свое действие путем: взаимодействия с антигенами раковых клеток; активации механизмов естественного иммунного ответа организма, оказывающего цитотоксический эффект; взаимодействия с антигенами, обеспечивающими пролиферацию или рост опухоли. Механизмы цитотоксического действия монокло- нальных антител, вызванные специфическим взаимодействием с рецепторами антигенов на опухолевых клетках, могут быть обусловлены: активацией компонентов комплемента; индукцией антитело-зависимой цитотоксичности; индукцией апоптоза; блокированием рецепторов и нарушением внутриклеточных сигнальных путей; ингибирова- нием биологически активных молекул для достижения фенотипа опухоли; индукцией идио- или антиидиотипиче- ского ответа; подавлением роста опухоли за счет уменьшения образования новых сосудов и т. д. Выводы. На основании механизмов и избирательного действия, влияния на звенья иммунной системы и фазы клеточного цикла, использовании современных биотехнологий, препараты моноклональных антител явля- ются перспективными противоопухолевыми средствами в персонализированной терапии рака. Ключевые слова: моноклональные антитела, противоопухолевая активность, онкологические заболевания, иммуноглобулины, антигены. Cancerul este a doua patologie ca incidență, circa lecule mari, sunt indiscutabile. Inițial AMC au țintit 18 milioane de cazuri noi, și cauză de deces, 9,5 mili- citokinele solubile, iar în prezent acționează și asupra oane anual, la nivel mondial. Se estimează, că la nivel receptorilor membranari, posedă un timp de înjumă- mondial în anul 2030 se vor depista până la 24 de tățire crescut și o acțiune mai complexă. Principiile milioane de cazuri noi. Actualmente terapia antican- farmacologiei au permis dezvoltarea unor molecule ceroasă clasică (radioterapie, chirurgie și chimiotera- terapeutice mici cu afinitate înaltă, selective și poten- pie sistemică), care cunoaște o dezvoltare continua în te, cu reducerea efectelor în afara țintei și interacțiu- ultimele decenii, prezintă un șir de dezavantaje ce le nilor medicamentoase. Concepte precum agonismul limitează tolerabilitatea și eficacitatea clinică. Cele complet și parțial, selectivitatea funcțională și modu- mai multe terapii anticanceroase până în prezent au lația alosterică au devenit din ce în ce mai relevante în fost concepute să interfereze cu factorii moleculari ai caracterizarea terapiei cu AMC. De rând cu AMC cu tumorigenezei, necesari pentru creșterea și progresia țintă unică s-au dezvoltat anticorpi conjugați, peptide tumorii. Chimioterapiile citotoxice existente de obicei terapeutice sintetice, ,,schele” alternative de AMC, vizează celulele canceroase cu proliferare rapidă îm- proteine de fuziune și AMC bi- și multi-specifici. An- piedicând diviziunea celulară prin influența la diferite ticorpii monoclonali au mai multe beneficii, precum etape ale ciclului celular. Totuși, acestea acționează mai puține efecte adverse, mai puține interacțiuni preponderant nespecific și afectează celule sănătoase medicamentoase, specificitate mai mare și eficacitate cu multiplicare rapidă, precum măduva osoasă, pro- potențial crescută prin terapie țintită [4, 12]. ducând reacții adverse severe. Obiectivul primordial Elaborarea, cercetarea și promovarea preparate- al terapiilor țintite este de a asigura o selectivitate mai lor anticorpilor monoclonali pentru tratamentul unei mare pentru a reduce efectele adverse [2, 3, 10]. game variate de maladii, inclusiv în patologia
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