Terapötik Nükleik Asitler ve Kanser Tedavisindeki Güncel Durumu
Özet
Kanser, küresel ölçekte milyonlarca insanı etkileyen ve geleneksel yöntemlerin yan etkileri ya da yetersizlikleri nedeniyle yeni arayışlara yol açan ciddi bir halk sağlığı sorunudur. Bu doğrultuda, doğrudan proteinler yerine onları kodlayan nükleik asitleri hedefleyen terapötik yaklaşımlar (ASO/antigen oligonükleotitler, siRNA, miRNA, ribozimler, aptamerler ve mRNA) modern ilaç araştırmalarında öne çıkmaktadır. Bu ajanlar, gen ekspresyonunu spesifik olarak baskılama, mutant proteinleri dönüştürme veya bağışıklık yanıtı oluşturma gibi karakteristik mekanizmalarla çalışırlar. Genetik ve nadir hastalıkların tedavisinde bazı nükleik asit ilaçları ve özellikle SARS-CoV-2'ye karşı geliştirilen mRNA aşıları FDA ile EMA'dan onay alarak klinikte başarı yakalamış olsa da, kanser tedavisinde durum henüz klinik deneme aşamasındadır. Kanser tedavisine yönelik birçok çalışma yürütülmekte, bazı antisens oligonükleotitler faz 3'e kadar ilerlemiş ve belirli siRNA ile mRNA adayları umut verici antitümör etkiler göstermiş olsa da, henüz onaylanmış bir nükleik asit bazlı kanser ilacı bulunmamaktadır. Canlı organizmada serum nükleazları tarafından hızla parçalanmaları, anyonik yapıları sebebiyle hücre penetrasyonlarının düşük olması ve serum proteinleriyle etkileşmeleri, bu terapötiklerin klinik başarısının önündeki temel biyolojik engellerdir. Bu engelleri aşmak adına, nükleik asitlerin hedef bölgeye verimli şekilde ulaşmasını sağlayacak biyouyumlu, toksik olmayan ve düşük immünojeniteli kimyasal modifikasyonlar ile akıllı ilaç taşıyıcı sistemlerin geliştirilmesine odaklanılmıştır.
Cancer remains a critical global public health problem that prompts new investigations due to the side effects or insufficiencies of traditional methods. Accordingly, therapeutic approaches targeting nucleic acids encoding proteins rather than the proteins themselves (ASO/antigen oligonucleotides, siRNA, miRNA, ribozymes, aptamers, and mRNA) stand out in modern drug research. These agents operate through characteristic mechanisms such as specifically suppressing gene expression, converting mutant proteins, or generating immune responses. Although some nucleic acid drugs for genetic and rare diseases, and particularly mRNA vaccines developed against SARS-CoV-2, have achieved clinical success by receiving FDA and EMA approvals, the status in cancer treatment is still in the clinical trial stage. Despite numerous ongoing studies for cancer therapy, where certain antisense oligonucleotides have advanced to phase 3 and specific siRNA and mRNA candidates have demonstrated promising antitumor effects, no nucleic acid-based cancer drug has been approved yet. Their rapid degradation by serum nucleases in vivo, low cell penetration due to their anionic nature, and interactions with serum proteins constitute the major biological barriers against their clinical success. To overcome these barriers, research has focused on developing chemical modifications and smart drug delivery systems that are biocompatible, non-toxic, and low in immunogenicity to ensure these nucleic acids reach the target site efficiently.
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