DNA Repair and the Carrier Ligand Specificity of Platinum Resistance

1996 ◽  
pp. 327-340
Author(s):  
Stephen G. Chaney ◽  
Edward L. Mamenta
Keyword(s):  
Dna Repair ◽  
Platinum Resistance ◽  
Ligand Specificity

scholarly journals DNA-repair ERCC1 Gene Polymorphisms in Epithelial Ovarian Cancer and Relation to Platinum Resistance and Survival

2011 ◽  
Vol 02 (02) ◽  
pp. 140-147 ◽  
Author(s):  
Karina Dahl Steffensen ◽  
Marianne Waldstrøm ◽  
Anders Jakobsen
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Epithelial Ovarian Cancer ◽  
Gene Polymorphisms ◽  
Platinum Resistance

scholarly journals Platinum Resistance: The Role of DNA Repair Pathways

2008 ◽  
Vol 14 (5) ◽  
pp. 1291-1295 ◽  
Author(s):  
Lainie P. Martin ◽  
Thomas C. Hamilton ◽  
Russell J. Schilder
Keyword(s):  
Dna Repair ◽  
Platinum Resistance ◽  
Repair Pathways

Limitations of the in vitro repair synthesis assay for probing the role of DNA repair in platinum resistance

1992 ◽  
Vol 81 (3) ◽  
pp. 223-231 ◽  
Author(s):  
Anne F. Nichols ◽  
Wendelyn J. Schmidt ◽  
Stephen G. Chaney ◽  
Aziz Sancar
Keyword(s):  
Dna Repair ◽  
Platinum Resistance ◽  
Repair Synthesis ◽  
In Vitro Repair

scholarly journals Platinum Resistance in Ovarian Cancer: Role of DNA Repair

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 119 ◽  
Author(s):  
Giovanna Damia ◽  
Massimo Broggini
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Dna Repair ◽  
Gynecological Cancer ◽  
Subsequent Treatment ◽  
Platinum Resistance ◽  
Acquired Drug Resistance ◽  
First Line Therapy ◽  
Dna Damaging Agents ◽  
Repair Mechanisms

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs.

scholarly journals The Prognostic Relevance of Poly (ADP-Ribose) Polymerase Expression in Ovarian Cancer Tissue of Wild Type and BRCA-Mutation Carrier Patients

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 144
Author(s):  
Szabolcs Molnár ◽  
Beáta Vida ◽  
Lívia Beke ◽  
Gábor Méhes ◽  
Róbert Póka
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Progression Free Survival ◽  
Platinum Resistance ◽  
Cancer Tissue ◽  
Wild Type ◽  
Ovarian Cancer Tissue ◽  
Mutation Carriers

(1) Background: The mechanism of platinum resistance in ovarian cancer is not fully clarified, but the properly functioning DNA repair mechanism can counteract the effect of conventional anticancer treatment. The objective of our study was to evaluate the expression of an important DNA repair enzyme, the Poly (ADP-Ribose) Polymerase (PARP) expression in epithelial ovarian cancer (EOC) tissues depending on BRCA status and to assess its relationship with platinum resistance. (2) Methods: Immunostaining to highlight PARP protein expression was performed using a rabbit polyclonal anti-PARP antibody. The intensity and distribution of immunostaining were assessed by light. Somatic BRCA1 or BRCA2 mutation carriers were identified with bidirectional sequencing of DNA from archived tumor tissue, if the test could not be performed due to technical reasons from tumor cells, the sequencing was done from peripheral blood cells to identify germline mutation carriers. The median progression-free survival (PFS) was generated for each semiquantitative group of PARP expression among chemotherapy-naive cases at the time of PARP immunohistochemistry. (3) Results: In the overall population, negative PARP immunohistochemistry predicted significant PFS (20.1 vs. 11.9 months, p = 0.001) and OS (49 vs. 114 months, p = 0.014) benefit. Genotype-stratified subgroup analysis in BRCA-negative cases confirmed the role of PARP positivity indicating an unfavorable prognosis in the entire population (relapsed 73.91% vs. 92%; OR: 4.06; p = 0.04). In the cases of the subgroup carrying the BRCA mutation, the presence of PARP expression was not associated with less favorable relapse rates, but with marginal significance for overall survival predicted a lower chance of survival (OS more than 32 months 72.73% vs. 35%; OR: 0.2; p = 0.05). (4) Conclusion: The BRCA wild type patients with strong expression of PARP enzymes before the first set of chemotherapy have a poor prognosis.

scholarly journals Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 56
Author(s):  
Adel Alblihy ◽  
Muslim L. Alabdullah ◽  
Reem Ali ◽  
Mashael Algethami ◽  
Michael S. Toss ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Cellular Localization ◽  
Progression Free Survival ◽  
Phase Cell ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Functional Evaluation ◽  
P Values ◽  
Ovarian Cancers

Platinum resistance seriously impacts on the survival outcomes of patients with ovarian cancers. Platinum-induced DNA damage is processed through DNA repair. NBS1 is a key DNA repair protein. Here, we evaluated the role of NBS1 in ovarian cancers. NBS1 expression was investigated in clinical cohorts (protein level (n = 331) and at the transcriptomic level (n = 1259)). Pre-clinically, sub-cellular localization of NBS1 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. NBS1 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. Nuclear NBS1 overexpression was associated with platinum resistance (p = 0.0001). In univariate and multivariate analysis, nuclear NBS1 overexpression was associated with progression free survival (PFS) (p-values = 0.003 and 0.017, respectively) and overall survival (OS) (p-values = 0.035 and 0.009, respectively). NBS1 mRNA overexpression was linked with poor PFS (p = 0.011). Pre-clinically, following cisplatin treatment, we observed nuclear localization of NBS1 in A2780cis and PEO4 compared to A2780 and PEO1 cells. NBS1 depletion increased cisplatin cytotoxicity, which was associated with accumulation of double strand breaks (DSBs), S-phase cell cycle arrest, and increased apoptosis. NBS1 is a predictor of platinum sensitivity and could aid stratification of ovarian cancer therapy.

Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov
Keyword(s):  
Oxidative Stress ◽  
Head And Neck ◽  
Transcriptional Activation ◽  
Platinum Resistance ◽  
Mrna Levels ◽  
Strong Positive Correlation ◽  
Platinum Compounds ◽  
Copper Chelation ◽  
Novel Approach ◽  
Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

259: Dna-Repair Genetic Polymorphisms and Prostate Cancer Risk

2005 ◽  
Vol 173 (4S) ◽  
pp. 71-71
Author(s):  
Peter E. Clark ◽  
M. Craig Hall ◽  
Kristin L. Lockett ◽  
Jianfeng Xu ◽  
Sigun L. Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Risk ◽  
Genetic Polymorphisms ◽  
Prostate Cancer Risk
Sign in / Sign up

Export Citation Format

Share Document