DIŞA ATIM POMPA SİSTEMLERİ VE BU SİSTEMLERİN KANSER TEDAVİSİNDEKİ ETKİNLİKLERİ

ÖZET Membranlar hücreleri çevresinde ayıran, lipit, proteinler ve karbonhidratlardan oluşan çift tabakalı yapılardır. Çeşitli moleküllerin hücre zarı boyunca taşınmasını sağlayan sistemler arasında hücre zarına yerleşmiş taşıyıcı proteinler bulunmaktadır. Kanser, kontrolsüz hücre çoğalmasıyla karakterize bir grup hastalığın genel adıdır. Ortalama ömrün uzaması gibi çeşitli etkenler ile kanser görülme sıklığı artmaktadır. Kanserin tedavisi önündeki en önemli engellerden bir tanesi, kanser hücrelerinin kemoterapötiklere karşı geliştirdikleri çoklu ilaç direncidir. Bu dirence sebep olan en önemli etkenlerden birisi ABC taşıyıcı proteinleridir. Günümüze kadar keşfedilmiş 49 üyesi bulunan bu protein süper ailesinin, in vivo şartlarda çoklu ilaç direnci ile ilişkili olduğu belirlenmiş 4 üyesi bulunmaktadır. Bunlar P-glikoprotein (MDR1), çoklu ilaç direnci ilişkili protein (MRP1), göğüs kanseri direnç proteini (BCRP) ve ABCC10’dur. Bu proteinler, kimyasal yapısı ve etki mekanizmaları bakımından birbirinden çok farklı pek çok antikanser ilacını hücre dışına atarak, kanser hücrelerinin kemoterapötiklere direnç geliştirmesine neden olmaktadır. Kanser hücrelerinde oluşan çoklu ilaç direncini atlatmak ve bu hücreleri antikanser ilaçlarına tekrar duyarlı hale getirmek için denenen stratejilerden birisi, antikanser ilaçların p-gp inhibitörleri ile birlikte verilmesidir. Bu amaçla 3 nesil p-gp inhibitörü geliştirilmiştir. Henüz klinik çalışmalarda başarı gösteremeyen bu inhibitörler, kanser tedavisi açısından üzerinde durulması gereken çok önemli bir alanı oluşturmaktadır. ABSTRACT Membranes, which separate the cells from their environment, are two-layered structures composed of lipits, proteins and carbohydrates. One of the systems that allow the transport of various molecules accros cell membranes are carrier proteins that are located on the cell membrane. Cancer is the general name of a group of diseases characterized by uncontrolled cell proliferation. The incidence of cancer is increasing with various factors such as the average life span. One of the most important obstacles to cancer treatment is multidrug resistance, which cancer cells develop against chemotherapeutics. ABC carrier proteins are one of the most important factors that cause this resistance. Until today 49 members of this protein superfamily has been discovered, there are 4 members who are found to be associated with multiple drug resistance in vivo conditions. These are P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP1), breast cancer resistance protein (BCRP) and ABCC10. These proteins can efflux many different anticancer drugs which are different from each other in terms of chemical structure and mechanism of action and cause cancer cells to develop resistance to chemotherapeutics. One strategy that has been tried to overcome the multiple drug resistance that occurs in cancer cells and make these cells susceptible to anticancer drugs is the co-administration of anticancer drugs with p-gp inhibitors. Three generations of p-gp inhibitors have been developed for this purpose. These inhibitors, which have not yet been successful in clinical trials, constitute a very important area to be addressed in terms of cancer treatment.

Anahtar Kelimeler:

ABC taşıyıcılar, çoklu ilaç direnci

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