LIVIVO - Search results -

Search results

Result 1 - 10 of total 26

Search options

Article ; Online: Association of changes in expression of

Krushkal, Julia / Zhao, Yingdong / Roney, Kyle / Zhu, Weimin / Brooks, Alan / Wilsker, Deborah / Parchment, Ralph E / McShane, Lisa M / Doroshow, James H

Epigenetics

2024 Volume 19, Issue 1, Page(s) 2309824

Abstract: Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such ... ...

Abstract	Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of
MeSH term(s)	Dasatinib/pharmacology ; DNA Methylation ; Cell Line, Tumor ; Sirtuins/genetics ; Sirtuins/metabolism ; Antineoplastic Agents/pharmacology ; Histone Deacetylase Inhibitors/pharmacology ; Neoplasms/drug therapy ; Neoplasms/genetics
Chemical Substances	Dasatinib (RBZ1571X5H) ; Sirtuins (EC 3.5.1.-) ; Antineoplastic Agents ; Histone Deacetylase Inhibitors
Language	English
Publishing date	2024-02-18
Publishing country	United States
Document type	Journal Article
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.1080/15592294.2024.2309824
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article: PARP Inhibitor Applicability: Detailed Assays for Homologous Recombination Repair Pathway Components.

O'Sullivan Coyne, Geraldine / Karlovich, Chris / Wilsker, Deborah / Voth, Andrea Regier / Parchment, Ralph E / Chen, Alice P / Doroshow, James H

OncoTargets and therapy

2022 Volume 15, Page(s) 165–180

Abstract: Poly(ADP-ribose) polymerase inhibitors (PARPi) have been in clinical use since 2014 for certain patients with ... ...

Abstract	Poly(ADP-ribose) polymerase inhibitors (PARPi) have been in clinical use since 2014 for certain patients with germline
Language	English
Publishing date	2022-02-24
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2495130-4
ISSN	1178-6930
ISSN	1178-6930
DOI	10.2147/OTT.S278092
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors.

Mittra, Arjun / Coyne, Geraldine H O' Sullivan / Zlott, Jennifer / Kummar, Shivaani / Meehan, Robert / Rubinstein, Lawrence / Juwara, Lamin / Wilsker, Deborah / Ji, Jiuping / Miller, Brandon / Navas, Tony / Ferry-Galow, Katherine V / Voth, Andrea Regier / Chang, Ting-Chia / Jiwani, Shahanawaz / Parchment, Ralph E / Doroshow, James H / Chen, Alice P

Cancer chemotherapy and pharmacology

2023 Volume 93, Issue 3, Page(s) 177–189

Abstract: Purpose: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2‑negative, locally advanced or metastatic breast cancer. ... ...

Abstract	Purpose: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2‑negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546). Methods: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations. The primary objective was to examine the PD effects of talazoparib; the secondary objective was to determine overall response rate (ORR). Tumor biopsies were mandatory at baseline and post-treatment on day 8 (optional at disease progression). Biopsies were analyzed for PARylation, DNA damage response (γH2AX), and epithelial‒mesenchymal transition. Results: Nine patients enrolled in this trial. Four of six patients (67%) evaluable for the primary PD endpoint exhibited a nuclear γH2AX response on day 8 of treatment, and five of six (83%) also exhibited strong suppression of PARylation. A transition towards a more mesenchymal phenotype was seen in 4 of 6 carcinoma patients, but this biological change did not affect γH2AX or PAR responses. The ORR was 55% with the five partial responses lasting a median of six cycles. Conclusion: Intra-tumoral DNA damage response and inhibition of PARP enzymatic activity were confirmed in patients with advanced solid tumors harboring BRCA1/2 mutations after 8 days of talazoparib treatment.
MeSH term(s)	Adult ; Female ; Humans ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Leukocytes, Mononuclear ; Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/genetics
Chemical Substances	Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; talazoparib (9QHX048FRV)
Language	English
Publishing date	2023-11-27
Publishing country	Germany
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-023-04600-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1420: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: ATR inhibition reverses the resistance of homologous recombination deficient MGMT

El Touny, Lara H / Hose, Curtis / Connelly, John / Harris, Erik / Monks, Anne / Dull, Angie B / Wilsker, Deborah F / Hollingshead, Melinda G / Gottholm-Ahalt, Michelle / Alcoser, Sergio Y / Mullendore, Michael E / Parchment, Ralph E / Doroshow, James H / Teicher, Beverly A / Rapisarda, Annamaria

Oncotarget

2021 Volume 12, Issue 21, Page(s) 2114–2130

Abstract: The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all ... ...

Abstract	The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMT
Language	English
Publishing date	2021-10-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.28090
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Chk1 phosphorylation during mitosis: a new role for a master regulator.

Wilsker, Deborah / Bunz, Fred

Cell cycle (Georgetown, Tex.)

2009 Volume 8, Issue 8, Page(s) 1161–1163

Abstract: The human DNA damage responses are modulated by both nonessential and essential pathways. The extensively studied ATM kinase and p53 are examples of the former. While loss-of-function mutations in genes that encode ATM and p53 cause marked ... ...

Abstract	The human DNA damage responses are modulated by both nonessential and essential pathways. The extensively studied ATM kinase and p53 are examples of the former. While loss-of-function mutations in genes that encode ATM and p53 cause marked predispositions to cancer, the loss of these proteins does not appear to impact basic cell growth and proliferation. In contrast, the checkpoint kinase Chk1 and its upstream activator ATR are essential.(1-4) What do these proteins do in undamaged cells?
MeSH term(s)	Animals ; CDC2 Protein Kinase/metabolism ; Checkpoint Kinase 1 ; DNA Replication ; Humans ; Mitosis ; Phosphorylation ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; cdc25 Phosphatases/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; CDC2 Protein Kinase (EC 2.7.11.22) ; cdc25 Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2009-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.8.8.8148
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5881: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Translating pharmacodynamic biomarkers from bench to bedside: analytical validation and fit-for-purpose studies to qualify multiplex immunofluorescent assays for use on clinical core biopsy specimens.

Marrero, Allison / Lawrence, Scott / Wilsker, Deborah / Voth, Andrea Regier / Kinders, Robert J

Seminars in oncology

2016 Volume 43, Issue 4, Page(s) 453–463

Abstract: Multiplex pharmacodynamic (PD) assays have the potential to increase sensitivity of biomarker-based reporting for new targeted agents, as well as revealing significantly more information about target and pathway activation than single-biomarker PD assays. ...

Abstract	Multiplex pharmacodynamic (PD) assays have the potential to increase sensitivity of biomarker-based reporting for new targeted agents, as well as revealing significantly more information about target and pathway activation than single-biomarker PD assays. Stringent methodology is required to ensure reliable and reproducible results. Common to all PD assays is the importance of reagent validation, assay and instrument calibration, and the determination of suitable response calibrators; however, multiplex assays, particularly those performed on paraffin specimens from tissue blocks, bring format-specific challenges adding a layer of complexity to assay development. We discuss existing multiplex approaches and the development of a multiplex immunofluorescence assay measuring DNA damage and DNA repair enzymes in response to anti-cancer therapeutics and describe how our novel method addresses known issues.
MeSH term(s)	Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/analysis ; Biopsy, Large-Core Needle ; Calibration ; Chemistry, Clinical/methods ; DNA Repair/drug effects ; DNA Repair/physiology ; Enzymes/analysis ; Enzymes/metabolism ; Fluorescent Antibody Technique/methods ; Fluorescent Antibody Technique/standards ; Humans ; Image Processing, Computer-Assisted ; Neoplasms/drug therapy ; Neoplasms/pathology ; Protein Array Analysis/methods ; Quality Control ; Reproducibility of Results
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Enzymes
Language	English
Publishing date	2016-06-14
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	189220-4
ISSN	1532-8708 ; 0093-7754
ISSN (online)	1532-8708
ISSN	0093-7754
DOI	10.1053/j.seminoncol.2016.06.003
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1348: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells.

Wilsker, Deborah / Chung, Jon H / Bunz, Fred

Cell cycle (Georgetown, Tex.)

2012 Volume 11, Issue 8, Page(s) 1564–1572

Abstract: Many cancer cells are unable to maintain a numerically stable chromosome complement. It is well established that aberrant cell division can generate progeny with increased ploidy, but the genetic factors required for maintenance of diploidy are not well ... ...

Abstract	Many cancer cells are unable to maintain a numerically stable chromosome complement. It is well established that aberrant cell division can generate progeny with increased ploidy, but the genetic factors required for maintenance of diploidy are not well understood. Using an isogenic model system derived by gene targeting, we examined the role of Chk1 in p53-proficient and -deficient cancer cells. Targeted inactivation of a single CHK1 allele in stably diploid cells caused an elevated frequency of mitotic bypass if p53 was naturally mutated or experimentally disrupted by homologous recombination. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis. These aberrant cell cycles resulted in whole-genome endoreduplication and tetraploidization. The unscheduled bypass of mitosis could be suppressed by targeted reversion of a p53 mutation or by exogenous expression of Cdk1. In contrast, the number of tetraploid cells was not increased in isogenic cell populations that harbor hypomorphic ATR mutations, suggesting that suppression of unscheduled mitotic bypass is a distinct function of Chk1. These results are consistent with a recently described role for Chk1 in promoting the expression of genes that promote cell cycle transitions and demonstrate how Chk1 might prevent tetraploidization during the cancer cell cycle.
MeSH term(s)	Alleles ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Checkpoint Kinase 1 ; DNA Damage ; Diploidy ; HCT116 Cells ; Haploinsufficiency ; Homologous Recombination ; Humans ; Metaphase ; Mitosis ; Mutation ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; Tetraploidy ; Tumor Suppressor Protein p53/deficiency ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cell Cycle Proteins ; Tumor Suppressor Protein p53 ; Protein Kinases (EC 2.7.-) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2012-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.19944
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5881: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival.

Wilsker, Deborah / Bunz, Fred

Molecular cancer therapeutics

2007 Volume 6, Issue 4, Page(s) 1406–1413

Abstract: The diverse responses of human cells to various forms of DNA damage are controlled by a complex network of signaling proteins. There has been considerable interest in the components of this signaling apparatus as potential targets for new forms of ... ...

Abstract	The diverse responses of human cells to various forms of DNA damage are controlled by a complex network of signaling proteins. There has been considerable interest in the components of this signaling apparatus as potential targets for new forms of anticancer therapy. In this report, we examine the contributions of an upstream signaling molecule, the ataxia telangiectasia mutated- and Rad3-related (ATR) protein kinase, to the resistance of cancer cells to DNA-damaging agents that are commonly used as anticancer therapeutics. Loss of ATR function in knock-in cancer cells strikingly enhanced the effects of several of the most commonly used therapeutic compounds, impeding the progression of the cell cycle and reducing long-term cancer cell survival. Loss of ATR function potentiated the toxicity of alkylating agents most strikingly, antimetabolites moderately, and double-strand break-inducing agents to a lesser extent. These results suggest that specific inhibition of ATR activity will be a valid strategy to increase the effectiveness of currently used modes of therapy.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Drug Synergism ; Enzyme Activation/drug effects ; Fluorouracil/pharmacology ; Genotype ; HCT116 Cells ; Humans ; Neoplasms/drug therapy ; Neoplasms/pathology ; Phosphoinositide-3 Kinase Inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Tumor Stem Cell Assay
Chemical Substances	Antineoplastic Agents ; Cell Cycle Proteins ; Phosphoinositide-3 Kinase Inhibitors ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2007-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-06-0679
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5750: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

Chen, Alice P / Sharon, Elad / O'Sullivan-Coyne, Geraldine / Moore, Nancy / Foster, Jared C / Hu, James S / Van Tine, Brian A / Conley, Anthony P / Read, William L / Riedel, Richard F / Burgess, Melissa A / Glod, John / Davis, Elizabeth J / Merriam, Priscilla / Naqash, Abdul R / Fino, Kristin K / Miller, Brandon L / Wilsker, Deborah F / Begum, Asma /

Ferry-Galow, Katherine V / Deshpande, Hari A / Schwartz, Gary K / Ladle, Brian H / Okuno, Scott H / Beck, Jill C / Chen, James L / Takebe, Naoko / Fogli, Laura K / Rosenberger, Christina L / Parchment, Ralph E / Doroshow, James H

The New England journal of medicine

2023 Volume 389, Issue 10, Page(s) 911–921

Abstract: Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.: Methods: We conducted an investigator- ... ...

Abstract	Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. Methods: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. Results: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. Conclusions: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).
MeSH term(s)	Adolescent ; Adult ; Child ; Humans ; Infant, Newborn ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; Body Weight ; Sarcoma, Alveolar Soft Part/drug therapy ; Administration, Intravenous
Chemical Substances	Antibodies, Monoclonal, Humanized ; atezolizumab (52CMI0WC3Y) ; B7-H1 Antigen
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMoa2303383
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Ua VI Zs.34: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers.

Wilsker, Deborah F / Barrett, Allison M / Dull, Angie B / Lawrence, Scott M / Hollingshead, Melinda G / Chen, Alice / Kummar, Shivaani / Parchment, Ralph E / Doroshow, James H / Kinders, Robert J

Clinical cancer research : an official journal of the American Association for Cancer Research

2019 Volume 25, Issue 10, Page(s) 3084–3095

Abstract: Purpose: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement.: Experimental design: We evaluated the time course and spatial ... ...

Abstract	Purpose: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement. Experimental design: We evaluated the time course and spatial activation of 3 protein biomarkers of DNA damage recognition and repair (γH2AX, pS343-Nbs1, and Rad51) simultaneously in a quantitative multiplex immunofluorescence assay (IFA) to assess DDR pathway activation in tumor tissues following exposure to DNA-damaging agents. Results: Because of inherent biological variability, baseline DDR biomarker levels were evaluated in a colorectal cancer microarray to establish clinically relevant thresholds for pharmacodynamic activation. Xenograft-bearing mice and clinical colorectal tumor biopsies obtained from subjects exposed to DNA-damaging therapeutic regimens demonstrated marked intratumor heterogeneity in the timing and extent of DDR biomarker activation due, in part, to the cell-cycle dependency of DNA damage biomarker expression. Conclusions: We have demonstrated the clinical utility of this DDR multiplex IFA in preclinical models and clinical specimens following exposure to multiple classes of cytotoxic agents, DNA repair protein inhibitors, and molecularly targeted agents, in both homologous recombination-proficient and -deficient contexts. Levels exceeding 4% nuclear area positive (NAP) γH2AX, 4% NAP pS343-Nbs1, and 5% cells with ≥5 Rad51 nuclear foci indicate a DDR activation response to treatment in human colorectal cancer tissue. Determination of effect-level cutoffs allows for robust interpretation of biomarkers with significant interpatient and intratumor heterogeneity; simultaneous assessment of biomarkers induced at different phases of the DDR guards against the risk of false negatives due to an ill-timed biopsy.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/metabolism ; Cell Cycle Proteins/metabolism ; Clofarabine/pharmacology ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; DNA Damage ; DNA Repair ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; HCT116 Cells ; HT29 Cells ; Histones/metabolism ; Humans ; Mice ; Mice, Nude ; Nuclear Proteins/metabolism ; Rad51 Recombinase/metabolism ; Topotecan/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Cell Cycle Proteins ; H2AX protein, human ; Histones ; NBN protein, human ; Nuclear Proteins ; Deoxycytidine (0W860991D6) ; Clofarabine (762RDY0Y2H) ; Topotecan (7M7YKX2N15) ; gemcitabine (B76N6SBZ8R) ; RAD51 protein, human (EC 2.7.7.-) ; Rad51 Recombinase (EC 2.7.7.-)
Language	English
Publishing date	2019-02-21
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-18-2523
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4223: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

To top

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito