Inhibiting PARP as a Strategic Target in Cancer PDF Download

Author: Christina Annunziata
Publisher: Frontiers Media SA
ISBN: 288919955X
Category : Medicine (General)
Languages : en
Pages : 99

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Book Description
Poly-ADP ribose polymerase (PARP) proteins are critical mediators of DNA repair. Many traditional anti-cancer chemotherapy agents overwhelm a cell’s ability to repair DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Breast, ovarian and other cancers develop in the setting of inherited DNA repair deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as to inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in hereditary DNA repair-deficient tumors. At the current time, mutation of BRCA serves as a potential, but not comprehensive, biomarker to predict response to PARP inhibitor therapy. Mechanisms of resistance to PARP inhibitors are only recently being uncovered. Future studies seek to identify sporadic cancers that harbor genomic instability rendering susceptibility to PARP inhibitors that compound lethal DNA damage.

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Languages : en
Pages : 0

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Book Description
Poly-ADP ribose polymerase (PARP) proteins are critical mediators of DNA repair. Many traditional anti-cancer chemotherapy agents overwhelm a cell's ability to repair DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Breast, ovarian and other cancers develop in the setting of inherited DNA repair deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as to inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in hereditary DNA repair-deficient tumors. At the current time, mutation of BRCA serves as a potential, but not comprehensive, biomarker to predict response to PARP inhibitor therapy. Mechanisms of resistance to PARP inhibitors are only recently being uncovered. Future studies seek to identify sporadic cancers that harbor genomic instability rendering susceptibility to PARP inhibitors that compound lethal DNA damage.

Author: Nicola J. Curtin
Publisher: Humana Press
ISBN: 3319141511
Category : Medical
Languages : en
Pages : 590

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Book Description
PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair. In addition, a description of discovery of the PARP family, and other DNA maintenance-associated PARPs will also be discussed. The volume also features a section on accessible chemistry behind the development of inhibitors. PARP inhibitors are a group of pharmacological inhibitors that are a particularly good target for cancer therapy. PARP plays a pivotal role in DNA repair and may contribute to the therapeutic resistance to DNA damaging agents used to treat cancer. Researchers have learned a tremendous amount about the biology of PARP and how tumour-specific defects in DNA repair can be exploited by PARPi. The “synthetic lethality” of PARPi is an exciting concept for cancer therapy and has led to a heightened activity in this area.

Author: David A. Frank
Publisher: Springer Science & Business Media
ISBN: 1402073402
Category : Medical
Languages : en
Pages : 358

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Book Description
One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

Author: Alexander Bürkle
Publisher: Springer Science & Business Media
ISBN: 0387360050
Category : Medical
Languages : en
Pages : 260

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Book Description
This is the most comprehensive, up-to-date reference on this post-translational modification of proteins, which is intimately linked with DNA repair, maintenance of genomic stability, transcriptional regulation, cell death and a variety of other cellular phenomena as well as with a variety of pathophysiological conditions, including ischemia-reperfusion damage, Parkinson’s disease, Type I diabetes mellitus, hemorrhagic and septic shock and other inflammatory conditions. Richly illustrated, it offers 19 chapters written by international experts.

Author: Jei Zhang
Publisher: CRC Press
ISBN: 1420042408
Category : Medical
Languages : en
Pages : 363

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Book Description
Recent research in cell death mechanisms has rekindled interest in PARP's (Poly (ADP-Ribose) Polymerase) intriguing role in necrosis and apoptosis. While the details of how PARP1 functions are still being elucidated, it has tremendous potential as a promising drug target. PARP inhibitors' dual actions of preventing cell death and abating inflammati

Author: Elliot Goodfellow
Publisher:
ISBN:
Category :
Languages : en
Pages :

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"According to the most recent Canadian statistics, the expected likelihood of women developing either breast or ovarian cancer throughout their lifetime is 26.1% and 2.9% respectively. Furthermore, breast cancer in women is the most prominent in the list of expected cancer development and its percentage is approximately twofold that of second place: lung cancer. Common to both men and women, pancreatic cancer has a 2.4% and 2.5% incidence of development respectively. In the previous decade, a commonality in these cancers has been discovered. in that a mutation in DNA repair proteins known as BRCA1 and 2 renders these gene products non-functional. A DNA repair protein, known as poly (ADP-Ribose) polymerase (PARP), then becomes the only means by which mutated cells with defective BRCA gene products can repair DNA. As a result, if PARP is inhibited within mutated cells with defective BRCA gene products, they become incapable of repairing DNA lesions and ultimately undergo cell death. This translated into a novel strategy for the selective therapy of tumours with cancer susceptibility gene termed "synthetic lethality". Despite the successful proof-of-concept for synthetic lethality in the clinic, acquired resistance have been reported. In order to enhance the potency of the approach, we sought to synthesize PARP inhibitors capable of not only blocking PARP function but also alkylating DNA. Thus, we identified EG40, a PARP inhibitor carrying a chloroethyltriazolinium moiety. Using the sulphorhodamine B (SRB) assays, we showed that EG40 is 2.5-fold more potent than its PARP inhibitor counterpart, PARP-4-ANI, and displays 25-fold selectivity for the BRCA2 mutant in an isogenic pair of cell lines. We assessed the binary targeting ability of EG40 using the comet assay to measure the extent of DNA damage, as well as using a PARP assay to measure the extent of PARP inhibition. EG40 inhibits PARP 20-fold more weakly when compared to the naked PARP-4-ANI scaffold and induces significant DNA damage against VC8 mutant cells. In conclusion, we have developed a drug that acts more effectively in terms of potency while maintaining selectivity for its counterpart. Furthermore this drug is effective in inhibiting PARP and causing DNA damage. This gives prima facie evidence that a single molecule termed combi-molecule with dual PARP-DNA targeting function can be highly effective in tumors containing BRCA1 or 2 mutations." --

Author: G.J.L. Kaspers
Publisher: Springer Science & Business Media
ISBN: 9780306460555
Category : Medical
Languages : en
Pages : 664

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Book Description
Cellular drug resistance is a major limitation to the success of chemotherapy of leu kemia and lymphoma. The importance of this has now been recognized by both clinicians and scientists. It is of utmost importance to bridge the gap between laboratory and clinic in this field of research. This is the main purpose of the series of International Symposia on Drug Resistance in Leukemia and Lymphoma. These are held every three years in Am sterdam, The Netherlands, since 1992. This book contains the proceedings of the third of these meetings, organised in 1998. The book covers all important aspects of drug resistance in leukemia and lymphoma, both in the form of extensive reviews as in manuscripts describing original data. General mechanisms of resistance are discussed, including the drug resistance related proteins p glycoprotein, MRP (multi-drug resistance protein) and LRP (lung resistance protein), and the role of glutathione and glutathione-S-transferases. Moreover, more drug type-specific mechanisms of resistance are a topic, such as for glucocorticoids and antifolates. Much in formation is provided on apoptosis and its regulators, and on the results of cell culture drug resistance assays. Several papers focus on the modulation or circumvention of drug resistance.

Author: Csaba Szabo
Publisher: CRC Press
ISBN: 1420038893
Category : Medical
Languages : en
Pages : 354

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Book Description
Poly (ADP-ribose) polymerase (PARP), also termed poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme with a wide range of functions, including regulation of DNA repair, cell differentiation, and gene expression. More than a decade after the identification of PARP-like enzymatic activities in mammalian cells, a novel role was proposed for this e

Author: Seigo Nakamura
Publisher: Springer Nature
ISBN: 9811645213
Category : Medical
Languages : en
Pages : 324

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Book Description
This highly informative and clearly written book presents the basic science and the latest data on hereditary breast and ovarian cancer (HBOC) to provide an up-to-date and holistic overview of the disease. It starts off by presenting the molecular mechanisms, genetic testing and counseling, and variants of unknown significance (VUS) to help readers understand the contemporary interpretation of the disease. Further chapters focus on the surveillance, diagnosis and treatment, including chemoprevention, risk reduction and drug development based on molecular mechanisms. It also includes a chapter on the latest findings from the HBOC database, ethical issues and the parp inhibitors, and discusses innovative thinking to manage and understand the disease. Hereditary Breast and Ovarian Cancer - Molecular Mechanism and Clinical Practice offers breast surgeons, medical oncologists, gynecological oncologists and genetic counselors a comprehensive overview of the disease. Providing insights into recent scientific findings and further avenues for investigation, it is also a thought-provoking and informative read for researchers and scholars.