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Claudia Spatari, Wenlong Li, Alfred H Schinkel, Gaetano Ragno, Jan H M Schellens, Jos H Beijnen, Rolf W Sparidans
A bio-analytical assay for the first third generation ALK inhibitor lorlatinib in mouse plasma was developed and validated. Ten-μl plasma samples were prepared by adding rucaparib as the internal standard and precipitation of the plasma proteins. For LC-MS/MS analysis, compounds were eluted at 0.5 mL/min and separated on a 3-μm particle-size, polar embedded octadecyl silica column by gradient elution using 0.1% of formic acid (in water) and methanol. Compounds were monitored with positive electrospray ionization using a triple quadrupole mass spectrometer in selected reaction monitoring mode...
March 9, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Pingping Fang, Jill A Madden, Lisa Neums, K Ryan Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in poly (ADP-ribose) polymerase (PARP) inhibitor response has not yet been studied. The present study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. Based on ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
Santosh R Alluri, Patrick J Riss
We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution. The binding of [3 H]rucaparib was found to be confined to PARP-expressing domains, for example, cerebellar cortex or hippocampal regions in both models...
March 16, 2018: ACS Chemical Neuroscience
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Sofia Genta, Massimo Aglietta, Anna Sapino, Giorgio Valabrega
BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis...
March 5, 2018: Recent Patents on Anti-cancer Drug Discovery
Xin He, Xin-Yang Li, Jing-Wei Liang, Chong Cao, Shuai Li, Ting-Jian Zhang, Fan-Hao Meng
Rucaparib and PJ34 were used as the structural model for the design of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units. And target compounds were successfully synthesized through a 3-step synthetic strategy. All target compounds were screened for their anti-proliferative effects against OVCAR-3 cell line. Preliminary biological study of these compounds provided potent compounds d21 and d22 with better activities than Rucaparib.
February 8, 2018: Bioorganic & Medicinal Chemistry Letters
Yongchang Lai, Zhenzhen Kong, Tao Zeng, Shaohong Xu, Xiaolu Duan, Shujue Li, Chao Cai, Zhijian Zhao, Wenqi Wu
Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion...
January 26, 2018: Oncology Reports
Britta Vormoor, Yvonne T Schlosser, Helen Blair, Abhishek Sharma, Sarah Wilkinson, David R Newell, Nicola Curtin
Background: DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality. Results: In clonogenic assays, single agent rucaparib LD50 values for continuously exposed cells were similar to those observed in HRR-defective cells (CAPAN-1 cell line, BRCA2 defective); however, both ES cell lines (TC-71, CADO-ES1) had functional HRR...
December 26, 2017: Oncotarget
Yuanli Zhen, Yonghao Yu
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response (DDR) mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies...
January 12, 2018: Biochemistry
Yu-Ting Wang, Bo Yuan, Hua-Dong Chen, Lin Xu, Yu-Nan Tian, Ao Zhang, Jin-Xue He, Ze-Hong Miao
With increasing uses of PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the PTEN-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46~71.78-fold) to all 5 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive...
December 22, 2017: Cancer Science
Mekonnen Sisay, Dumessa Edessa
Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining...
2017: Gynecologic Oncology Research and Practice
Xiaojun Liu, Yingjun Jiang, Billie Nowak, Bethany Qiang, Nancy Cheng, Yuling Chen, William Plunkett
PURPOSE: The mechanism of action of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors...
February 2018: Cancer Chemotherapy and Pharmacology
Donald C Moore, J Tanner Ringley, Jolly Patel
OBJECTIVE: To review the pharmacology, safety, efficacy, and the role of rucaparib in the treatment of relapsed, advanced ovarian cancer. SUMMARY: A total of 2 phase I/II trials and 1 phase II trial have evaluated the safety and efficacy of oral rucaparib in ovarian cancer. In patients with deleterious BRCA1/2 mutation, an overall response rate of 80% was achieved in the phase II trial Assessment of Rucaparib in Ovarian CancEr Trial 2 (ARIEL2). In the same trial, progression-free survival was higher in patients with BRCA1/2 mutation and BRCA wild types with high loss of heterozygosity (LOH) than BRCA wild types with low LOH...
January 1, 2017: Journal of Pharmacy Practice
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA -mutant ovarian cancer...
2017: OncoTargets and Therapy
Maryam Zanjirband, Nicola Curtin, Richard J Edmondson, John Lunec
Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials...
September 19, 2017: Oncotarget
Christine Walsh
INTRODUCTION: PARP (poly(ADP-ribose) polymerase) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials evaluating PARP inhibitor therapy in ovarian cancer as monotherapy, maintenance therapy after partial or complete remission to therapy or as a part of a combination regimen. EVIDENCE ACQUISITION: PubMed,, data from the United States Food and Drug Administration (US FDA) and proceedings from scientific conferences were searched for published and unpublished data pertaining to clinical trials and approvals of PARP inhibitor use in ovarian cancer...
October 9, 2017: Minerva Ginecologica
Elise C Kohn, Jung-Min Lee, S Percy Ivy
Rucaparib, a polyADPribose polymerase inhibitor (PARPi), was approved recently for use in women with high-grade serous ovarian cancer (HGSOC). It is now one of three approved PARPi for use in recurrent ovarian cancer, a family of agents that has changed the HGSOC treatment landscape and outcome. Clin Cancer Res; 23(23); 7155-7. ©2017 AACR See related article by Balasubramaniam et al., p. 7165 .
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Robert L Coleman, Amit M Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W Holloway, Margarita Amenedo Gancedo, Peter C Fong, Jeffrey C Goh, David M O'Malley, Deborah K Armstrong, Jesus Garcia-Donas, Elizabeth M Swisher, Anne Floquet, Gottfried E Konecny, Iain A McNeish, Clare L Scott, Terri Cameron, Lara Maloney, Jeff Isaacson, Sandra Goble, Caroline Grace, Thomas C Harding, Mitch Raponi, James Sun, Kevin K Lin, Heidi Giordano, Jonathan A Ledermann
BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries...
October 28, 2017: Lancet
Amit M Oza, Anna V Tinker, Ana Oaknin, Ronnie Shapira-Frommer, Iain A McNeish, Elizabeth M Swisher, Isabelle Ray-Coquard, Katherine Bell-McGuinn, Robert L Coleman, David M O'Malley, Alexandra Leary, Lee-May Chen, Diane Provencher, Ling Ma, James D Brenton, Gottfried E Konecny, Cesar M Castro, Heidi Giordano, Lara Maloney, Sandra Goble, Kevin K Lin, James Sun, Mitch Raponi, Lindsey Rolfe, Rebecca S Kristeleit
OBJECTIVE: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy...
November 2017: Gynecologic Oncology
Jin Young Kim, Chi Heum Cho, Hong Suk Song
Epithelial ovarian cancer is the eighth most common cause of cancer-related deaths in women because most patients present with advanced stage disease at the time of diagnosis. Although cytoreductive surgery and platinum-based chemotherapy remain the gold standards of treatment, the recurrence rate of ovarian cancer remains high. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug have failed to affect either progression-free survival or overall survival and have resulted in an increase in toxic side effects...
September 2017: Korean Journal of Internal Medicine
Sevil Korkmaz-Icöz, Bartosz Szczesny, Michela Marcatti, Shiliang Li, Mihály Ruppert, Felix Lasitschka, Sivakkanan Loganathan, Csaba Szabo, Gábor Szabó
BACKGROUND AND PURPOSE: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation. EXPERIMENTAL APPROACH: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2 O2 ) or with glucose-oxidase (GOx, which generates H2 O2 in the tissue culture medium)...
August 14, 2017: British Journal of Pharmacology
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