Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is available to use as a template for repair. Because a template is available, HR is a high fidelity, error-free form of DNA repair. With NHEJ there is not a template and the DNA is trimmed and ligated which is a very error-prone process of repair which can lead to genetic instability. Exploiting these mechanism led to development of PARP inhibitors with the idea of utilizing synthetic lethality, where two deficiencies each having no effect on the cellular outcome become lethal when combined, as single agent in BRCA deficient patients or as chemotherapy/radiotherapy combinations to inhibit ssDNA repair. The recent approval of olaparib in BRCA deficient ovarian cancer patients in US and Europe has opened up a whole new treatment option for ovarian cancer patients. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future.
Keyphrases
- dna repair
- dna damage response
- dna damage
- cell cycle
- circulating tumor
- end stage renal disease
- cell free
- single molecule
- early stage
- ejection fraction
- chronic kidney disease
- locally advanced
- radiation therapy
- oxidative stress
- combination therapy
- cell proliferation
- mass spectrometry
- copy number
- peritoneal dialysis
- genome wide
- risk assessment
- prognostic factors
- gene expression
- solid phase extraction
- structural basis