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Targeting DNA Repair: PARP and Chk1 Inhibitors

Published on Oct 25, 2013
· DOI :10.1201/b15944-20
Peter Stephens5
Estimated H-index: 5
,
Ruth Plummer30
Estimated H-index: 30
Abstract
  • References (112)
  • Citations (0)
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#1M. W. AudehH-Index: 2
#2Richard T. PensonH-Index: 46
Last. Andrew TuttH-Index: 53
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5500 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced chemotherapy-refractory ovarian cancer. The secondary aim was to asse...
94 Citations
#1Otto Metzger-FilhoH-Index: 19
#2Andrew TuttH-Index: 53
Last. Martine Piccart-GebhartH-Index: 110
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Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chem...
226 CitationsSource
#1Jonathan A. Ledermann (UCL: University College London)H-Index: 48
#2Philipp Harter (University of Duisburg-Essen)H-Index: 37
Last. Ursula A. Matulonis (Harvard University)H-Index: 56
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randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% v...
789 CitationsSource
#1Anand G. Patel (Mayo Clinic)H-Index: 7
#2Silvana B. De Lorenzo (Mayo Clinic)H-Index: 3
Last. Scott H. KaufmannH-Index: 94
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Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free condi...
168 CitationsSource
#1Xuesong LiuH-Index: 28
#2Yan ShiH-Index: 23
Last. Alexander R. ShoemakerH-Index: 18
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Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD + )-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD + -competitive compounds with iniparib and its C -nitroso metabolite. Experimen...
133 CitationsSource
#1Andreas HöglundH-Index: 9
#2Lisa M. NilssonH-Index: 18
Last. Jonas A. NilssonH-Index: 21
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Purpose: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target ge ...
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#1K Gelmon (BC Cancer Agency)H-Index: 72
#2Marc Tischkowitz (JGH: Jewish General Hospital)H-Index: 4
Last. Amit M. OzaH-Index: 58
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Summary Background Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. Methods In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative br...
677 CitationsSource
#1Paula M. Fracasso (UVA: University of Virginia)H-Index: 26
#2Kerry J. Williams (WashU: Washington University in St. Louis)H-Index: 3
Last. Helen Piwnica-Worms (WashU: Washington University in St. Louis)H-Index: 62
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Purpose UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.
43 CitationsSource
#1Alan Loh HoH-Index: 9
#2Johanna C. BendellH-Index: 38
Last. Geoffrey I. ShapiroH-Index: 79
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3033 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has shown synergistic activity with irino in xenograft models. Methods: A 3+3 design evaluated the safety and PK of AZD7762 (6–144 mg iv) ± irino (100 or 125 mg/m2 iv) (NCT00473616). AZD7762 was given alone on days 1 and 8 (Cycle 0); after 7 days’ observation, AZD7762 was given after irino on days 1 and 8 of 21-day cycles until disease progression/discontinuation for any reason. To further confirm safety, an expansion phase was conducted at...
24 CitationsSource
3058 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gem in preclinical xenograft studies. Methods: This open-label, dose-escalation (3+3 design) study evaluated the safety, tolerability and PK of AZD7762 (6–40 mg iv) alone and combined with gem (750 or 1000 mg/m2 iv) (NCT00413686). Pts received AZD7762 alone on days 1 and 8 (Cycle 0) followed by 7 days’ observation, then AZD7762 + gem on days 1 and 8 of a 21-day cycle. Results: 42 pts (mean age 58 yea...
16 CitationsSource
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