EMİR BOZKURT, HARİKA ATMACA İLHAN, Selim UZUNOĞLU

Glioblastoma tümörlerinde çoklu ilaç direnci

Merkezi sinir sisteminin gerek yapı ve fonksiyonunu gerekse patolojisini hücresel düzeyde anlamada nöronal ve glial paradigma olmak üzere iki yaklaşım öne çıkmaktadır. Nöronal paradigma nöronları, glial paradigma ise glia hücrelerini vurgulayarak patolojiyi açıklamakta ve anlamlandırmaktadır. Beyin tümörlerinin en yaygın türlerinden biri olan glioblastoma, konumu, sağ kalım süresinin kısalığı ve ilacın hedef dokuya ulaşabilirliğinin zorluğu noktalarından özgün bir tümördür. Glioblastomalarda kemoterapötik tedavi- de gözlenen ilaç direnci, diğer tümörlerde gözlenen direnç mekanizmalarıyla uyumludur. Bu direnç mekanizmaları, tümör hücreleri- nin ilaca hassasiyetini azaltan (kan beyin bariyeri ve membran transport proteinlerine bağlı olarak hücre içine ilaç girişinin azalması, DNA tamir sistemlerindeki adaptif cevap ve hedef molekülün ilaca bağlanma etkinliğinin azaltılması) ve ilaçların hedef dokudaki et- kin konsantrasyonunu azaltan mekanizmalar (detoksifikasyonda rol alan proteinlerdeki değişimler, tümör mikroçevresinde meydana gelen hipoksik bölgeler) olmak üzere iki alt başlıkta incelenebilir. Ayrıca, onkogenlerin aktivasyonu ve apoptozisle ilişkili Bcl-2 ailesi proteinlerinin ifadesindeki düzensizliklerin de ilaç direncinin ortaya çıkışında rol aldığı bilinmektedir. Bu derlemede glioblastoma tümörlerinde görülen çoklu ilaç direncinin olası mekanizmalarını güncel literatür ışığında tanımlanarak sistemik ve bütüncül bir bakış açısı ortaya konulmaya çalışılmıştır

Multiple drug resistance in glioblastoma

In cellular perspective, neuronal and glial paradigms are two prevailing approaches for understanding both structure/function and pathology of central nervous system. Neuronal paradigm explains brain pathology mainly based on neurons, while glial paradigm put more emphasize to glial cells. Glioblastoma, one of the most common brain tumors, is unique due to its location, the shortness of median survival and the difficulty of efficient uptake in target tissue. Drug resistance mechanisms observed in the chemotherapy of glioblastoma are quite similar to the ones of other tumor types. These mechanisms can be investigated under two main groups: one is decreasing the sensitivity of tumor cells to chemotherapeutic agents (decreasing of drug uptake into cell by blood brain barrier and membrane transport proteins) and the other one is reducing the efficient concentration of the drug in target tissue (variabilities in detoxification proteins and hypoxia in the tumor microenvironment). Moreover, activation of oncogenes and abnormalities of expression of Bcl-2 protein family members are mediating players in the development of drug resistance in glioblastoma. In this review, the possible drug resistance mechanisms in glioblastoma were described in the light of recent literature by using systemic and integrative perspective

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