Poli (ADP-Riboz) Polimeraz İnhibitörleri
Özet
DNA hasar tamir mekanizmalarında kritik rol oynayan Poli (ADP-riboz) polimeraz (PARP) enzimi, özellikle tek iplikçikli DNA kırıklarının baz eksizyon tamiri (BER) yoluyla onarılmasından sorumludur. Hücrelerde homolog rekombinasyon eksikliği (HRD) gibi çift sarmal tamir kusurları bulunduğunda, PARP'ın da inhibe edilmesi hücreyi alternatifi olmayan bir ölüme sürükler; tıp literatüründe bu duruma "sentetik letalite" adı verilmektedir. Enzim ailesinin en önemli üyesi olan PARP1; DNA bağlanma, otomodifikasyon ve katalitik olmak üzere üç ana bölgeden oluşur ve hasar durumunda hızla aktive olarak süreci yönetir. Klinik pratikte nikotinamid analog yapısındaki olaparip, rucaparip, niraparip ve talazoparip gibi ajanlar FDA onayı alarak özellikle BRCA mutasyonu taşıyan over, meme, prostat ve pankreas kanserlerinin idame veya aktif tedavilerinde progresyonsuz sağkalımı anlamlı derecede uzatmıştır. Veliparip ise henüz onay alma aşamasında olup kombinasyon çalışmalarında değerlendirilmektedir. Bu inhibitörlerin kullanımı sırasında anemi, nötropeni ve trombositopeni gibi ciddi hematolojik yan etkiler ile yorgunluk ve bulantı gibi semptomlar gelişebilmekte, nadiren de olsa miyelodisplastik sendrom (MDS) ve akut miyeloid lösemi (AML) riskine yol açabilmektedir.
Poly (ADP-ribose) polymerase (PARP) enzymes play a vital role in DNA damage response, primarily taking part in the repair of single-strand DNA breaks via the base excision repair (BER) pathway. When cells harbor homologous recombination deficiency (HRD), inhibiting the PARP pathway deprives them of alternative repair routes, leading to cell death through a mechanism defined as "synthetic lethality". The most prominent member, PARP1, consists of three major domains: DNA-binding, automodification, and catalytic, and is rapidly activated upon detecting DNA lesions to maintain genomic integrity. In clinical oncology, several nicotinamide analogues including olaparib, rucaparib, niraparib, and talazoparip have received FDA approval, demonstrating significant improvements in progression-free survival as maintenance or primary therapy for BRCA-mutated ovarian, breast, prostate, and pancreatic cancers. Veliparib is currently in the approval pipeline and is being evaluated in various combination regimens. Despite their clinical efficacy, PARP inhibitors are frequently associated with severe hematological toxicities such as anemia, neutropenia, and thrombocytopenia, alongside fatigue and nausea, while carrying a rare but critical long-term risk for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
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