China
Africa
Explore chapters and articles related to this topic
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
One of the best-known DNA-repair enzymes is the zinc finger DNA-binding enzyme PARP-1 which becomes activated by sensing and binding to breaks mainly in single-stranded DNA, although it can also detect breaks in double-stranded DNA. For example, it can detect damage caused by exposure to topoisomerase inhibitors such as camptothecin and its derivatives, alkylating agents and cross-linking agents such as the platinum-based agents, or ionizing radiation. It then initiates DNA repair by recruiting and then ADP-ribosylating nuclear proteins such as the scaffold protein XRCC1 which directs POLB (DNA polymerase B) to replace a damaged nucleotide. Nuclear proteins associated with apoptosis may also be recruited. Therefore, the PARP-1 mediated poly(ADP-ribosyl)ation of nuclear proteins transforms DNA damage into signals that lead either to activation of repair processes such as the base-excision repair pathway or to cell death via apoptosis. There are over 16 variants of the PARP family of repair enzymes, although PARP-1 and PARP-2 are the most abundant and best studied.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Functionally, DNA strand breaks activate PARP protein. Some PARP proteins are vital for survival of cells, as evidenced by the lethality of the simultaneous absence of PARP 1 and PARP 2 or the simultaneous absence of TNKS or TNKS2 in murine models. By definition, PARP proteins must be able to transfer ADP-ribose from NAD+ to an acceptor protein and add multiple subunits of Poly(ADP) ribose (pADPr, PAR) [24]. It has not been proven that PARP 3 and PARP 4 form multiple subunits of PAR so they may not be PARP proteins [108]. In the homodimer state, the DBD recognizes and binds to sites of single strand DNA damage [35, 108, 113]. In addition to SSB repair, PARP is also involved in DSB repair. It attaches to DNA-protein kinase catalytic subunits (DNA-PK) Ku 70, and Ku80, to allow DSB repair through NHEJ DNA ligase [131]. PAR recruits ATM, MRE11, and topoisomerase 1, all involved in DSB repair [43, 44].
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Robert D. Morgan, Andrew R. Clamp, Gordon C. Jayson
In the last 10 years, poly(ADP-ribose) polymerase (PARP) inhibitors have changed the treatment of HGS ovarian cancer.84 Poly(ADP) ribose polymerase is a family of 17 different enzymes involved in a number of essential cellular mechanisms.85 It is the role of PARP-1 and PARP-2 in the response to DNA damage that has led to the utility of PARP inhibitors as anti-cancer therapy.86
Poly (ADP-ribose) polymerase inhibitors (PARPi) for advanced malignancies with multiple DNA-repair genetic aberrations
Published in Expert Review of Anticancer Therapy, 2022
Jian Hu, Peihe Liang, Dachun Jin, Runze Fan, Xiaodu Xie, Chuan Liu, Qing Jiang, Liang Gao
PARP is an enzyme family consisting of 17 members that regulate a variety of biological processes, including DNA damage repair. PARP1 is an abundant nuclear protein in cells that plays a vital role in repairing single-strand breaks (SSBs) and double-strand break (DSBs) [2]. PARP1 detects DNA SSBs and initiates their repair via the base excision repair pathway. PARPi, which inhibit the catalytic activity of PARP, impair the repair of DNA SSBs, thus leading to DSBs; then, these are repaired by HRR [3]. In addition, PARPi can trap PARP1 at the DNA level, leading to a replication blockade; Black et al. revised this exact mechanism from the molecular roots [4]. However, in tumor cells with HRR deficiency, such as loss-of-function mutations in BRCA1/2, DSBs would only have error-prone, low-fidelity repair pathways (non-homologous or microhomology-mediated end-joining (NHEJ or Alt-NHEJ) repair pathways) by default [5]. Thus, PARPi exerts an effect called ‘synthetic lethality’ in tumor cells with HRR deficiency, leading to an increase in genomic instability, cell-cycle arrest, and tumor-specific cell death (Figure 1).
Risk of fatigue with PARP inhibitors in cancer patients: a systematic review and meta-analysis of 29 phase II/III randomized controlled trials
Published in Journal of Chemotherapy, 2021
Poly ADP-ribose polymerase (PARP) inhibitors are currently one of the most promising treatment options for ovarian cancer and other tumor types. The family of PARP consists of 18 members and play a key role in the complex landscape of DNA repair mechanism.1 PARP are involved in recognizing single-strand DNA breaks (SSB) and their activation triggers DNA repair mechanisms, such as base excision repair.2 PARP inhibitors were used to improve the curative effect of chemotherapy drugs and as a treatment option for cancers that were mainly caused by DNA repair defects. Several PARP inhibitors have since been FDA approved for advanced ovarian cancer or breast cancer, such as olaparib in 2014, rucaparib in 2016, niraparib in 2017, and talazoparib in 2018.3,4 Moreover, some PARP inhibitors are under clinical study. Veliparib is a potent, orally bioavailable, PARP-1/2 inhibitor that showed anticancer effects in clinical trials.5
The impact of body composition on treatment in ovarian cancer: a current insight
Published in Expert Review of Clinical Pharmacology, 2021
Veronica McSharry, Kate Glennon, Amy Mullee, Donal Brennan
Poly (ADP-ribose) polymerase inhibitors (PARP) inhibitors have demonstrated promising results in trials of ovarian cancer and consistently demonstrate a progression-free survival benefit. PARP inhibitors block this DNA repair ability, thereby inhibiting the ability of tumor cells to repair DNA [18]. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation [19]. Subsequently, results of further phase III trials (PRIMA, PAOLA-1, VELIA) highlighted favorable results using first-line PARP inhibitors in patients with and without BRCA1/2 mutations [20–22]. As a consequence, FDA approval was given for the use of maintenance niraparib regardless of BRCA status and olaparib in combination with bevacizumab in homologous recombination deficient advanced ovarian cancer.