scholarly journals Examining the Role of Specialized DNA Polymerases in the Development of Temozolomide Resistance in Glioblastoma Multiforme

2021 ◽  
Vol 05 (02) ◽  
pp. 1-1
Author(s):  
Anthony J. Berdis ◽  
Keyword(s):  
Glioblastoma Multiforme ◽  
Dna Polymerases ◽  
Primary Brain Tumor ◽  
Dna Lesions ◽  
Current Standard ◽  
Cellular Mechanisms ◽  
Dna Lesion ◽  
Anti Cancer ◽  
Post Operative Survival

Glioblastoma multiforme (GBM) is an extremely malignant type of primary brain tumor that exhibits a high mortality rate. Current standard therapy involves surgery followed by radiation and treatment with the DNA-alkylating agent, temozolomide (TMZ). While TMZ treatment can extend post-operative survival, most patients develop resistance to TMZ which leads to a significant increase in mortality. At the molecular level, TMZ produces a variety of different DNA lesions including N7-methylguanine, N3-methyladenine, and O6-methylguanine. Although each DNA lesion possesses a unique molecular structure, they all elicit cytostatic and cytotoxic effects against GBM cells. This review article describes the molecular and cellular mechanisms accounting for the anti-cancer activity of TMZ as well as the mechanisms responsible for both inherent and TMZ-induced drug resistance. Special emphasis is placed on understanding the roles that various DNA polymerases play toward the initiation and progression of GBM in addition to mediating resistance to TMZ. This review concludes with discussions on several new approaches that show promise in combating TMZ-resistance, specifically using small molecules to block the replication of DNA lesions catalyzed by various DNA polymerases.

scholarly journals Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2911
Author(s):  
Miriam Navarrete-Miguel ◽  
Antonio Francés-Monerris ◽  
Miguel A. Miranda ◽  
Virginie Lhiaubet-Vallet ◽  
Daniel Roca-Sanjuán
Keyword(s):  
Electron Transfer ◽  
Energy Barrier ◽  
Ring Opening ◽  
Dna Lesions ◽  
Barrier Heights ◽  
Dna Lesion ◽  
Electron Reduction ◽  
The Stability ◽  
Electron Transfer Processes

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.

scholarly journals Radiotherapy of glioblastoma 15 years after the landmark Stupp’s trial: more controversies than standards?

2018 ◽  
Vol 52 (2) ◽  
pp. 121-128 ◽  
Author(s):  
Tomas Kazda ◽  
Adam Dziacky ◽  
Petr Burkon ◽  
Petr Pospisil ◽  
Marek Slavik ◽  
...  
Keyword(s):  
Concurrent Chemoradiotherapy ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Current Standard ◽  
Tumor Treating Fields ◽  
Integrated Boost ◽  
Hippocampal Sparing ◽  
New Treatment ◽  
Personalized Approach

Abstract Background The current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp’s landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp’s trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy. The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing. Conclusions In conjunction with new treatment approaches such as tumor-treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems.

Bevacizumab in combination with temozolomide in the adjuvant treatment of newly diagnosed glioblastoma multiforme: Preliminary results of a phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2016-2016
Author(s):  
M. K. Nicholas ◽  
R. V. Lucas ◽  
J. Arzbaecher ◽  
N. Paleologos ◽  
H. Krouwer ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Disease Progression ◽  
Primary Brain Tumor ◽  
Newly Diagnosed ◽  
Duration Of Treatment ◽  
Current Standard ◽  
Fractionated Radiotherapy ◽  
Macdonald Criteria ◽  
Tolerability Data ◽  
Gi Bleed

2016 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Current standard treatment consists of fractionated radiotherapy (RT) with daily oral temozolomide (TMZ) chemotherapy followed by 6 months of adjuvant TMZ chemotherapy. Median survival is 14.3 months. Because GBM is characterized by vascular proliferation and produces high levels of vascular endothelial growth factor (VEGF), attempts to better control the disease with targeted anti-angiogenesis therapies are underway. Here, we report preliminary safety and tolerability data of bevacizumab (BV) when added to monthly TMZ chemotherapy. Methods: Subjects received standard regional RT to a dose of 60 Gy in 30 fractions with dailyconcurrent TMZ (75 mg/m2) within 3–5 weeks of diagnosis. Four weeks after RT/TMZ, subjects received 5 consecutive daily TMZ doses (150–200 mg/m2) administered every 28 days. BV (10mg/kg) was given every 14 days. Treatment continued until either disease progression or unacceptable toxicity occurred. Results: 42 of 48 planned subjects were enrolled as of 12/30/08. Twenty-three remained on study. Of these, 4 were receiving RT/TMZ, 18 were receiving TMZ/BV and 1 was delayed post-RT/TMZ due to local wound infection. Nineteen were off-study. Eleven of those off-study never received BV due to: study withdrawal (n = 2), toxicity during RT/TMZ (n = 3) and post-RT/TMZ progression (n = 6). Seven subjects progressed while receiving TMZ/BV. Twenty-six of the 42 enrolled received at least one 28-day cycle of TMZ/BV (range 1 - 16 cycles). Duration of treatment, inclusive of RT/TMZ, ranged from 27 to 523 days. Best radiographic responses of evaluable subjects, using MacDonald criteria were: 5 complete, 9 partial, 13 stable and 7 progressive disease. Of those taken off study, 13 were due to disease progression. Of those removed from study due to toxicity, none were unexpected and only 1 (a GI bleed) occurred during the TMZ/BV phase. A statistical analysis of response and survival is pending. Conclusions: The co-administration of TMZ/BV following RT/TMZ for newly diagnosed GBM is safe and well-tolerated. [Table: see text]

scholarly journals Rev1 promotes replication through UV lesions in conjunction with DNA polymerases η, ι, and κ but not DNA polymerase ζ

2015 ◽  
Vol 29 (24) ◽  
pp. 2588-2602 ◽  
Author(s):  
Jung-Hoon Yoon ◽  
Jeseong Park ◽  
Juan Conde ◽  
Maki Wakamiya ◽  
Louise Prakash ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Crucial Role ◽  
Genome Stability ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Human Cells ◽  
Uv Lesions ◽  
Human And Mouse

Translesion synthesis (TLS) DNA polymerases (Pols) promote replication through DNA lesions; however, little is known about the protein factors that affect their function in human cells. In yeast, Rev1 plays a noncatalytic role as an indispensable component of Polζ, and Polζ together with Rev1 mediates a highly mutagenic mode of TLS. However, how Rev1 functions in TLS and mutagenesis in human cells has remained unclear. Here we determined the role of Rev1 in TLS opposite UV lesions in human and mouse fibroblasts and showed that Rev1 is indispensable for TLS mediated by Polη, Polι, and Polκ but is not required for TLS by Polζ. In contrast to its role in mutagenic TLS in yeast, Rev1 promotes predominantly error-free TLS opposite UV lesions in humans. The identification of Rev1 as an indispensable scaffolding component for Polη, Polι, and Polκ, which function in TLS in highly specialized ways opposite a diverse array of DNA lesions and act in a predominantly error-free manner, implicates a crucial role for Rev1 in the maintenance of genome stability in humans.

scholarly journals Somatic hypermutation of immunoglobulin genes: lessons from proliferating cell nuclear antigen K164R mutant mice

2008 ◽  
Vol 364 (1517) ◽  
pp. 621-629 ◽  
Author(s):  
Petra Langerak ◽  
Peter H.L Krijger ◽  
Marinus R Heideman ◽  
Paul C.M van den Berk ◽  
Heinz Jacobs
Keyword(s):  
B Cells ◽  
Proliferating Cell Nuclear Antigen ◽  
Somatic Mutations ◽  
Dna Polymerases ◽  
Critical Role ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Immunoglobulin Genes ◽  
Proliferating Cell

Proliferating cell nuclear antigen (PCNA) encircles DNA as a ring-shaped homotrimer and, by tethering DNA polymerases to their template, PCNA serves as a critical replication factor. In contrast to high-fidelity DNA polymerases, the activation of low-fidelity translesion synthesis (TLS) DNA polymerases seems to require damage-inducible monoubiquitylation (Ub) of PCNA at lysine residue 164 (PCNA-Ub). TLS polymerases can tolerate DNA damage, i.e. they can replicate across DNA lesions. The lack of proofreading activity, however, renders TLS highly mutagenic. The advantage is that B cells use mutagenic TLS to introduce somatic mutations in immunoglobulin (Ig) genes to generate high-affinity antibodies. Given the critical role of PCNA-Ub in activating TLS and the role of TLS in establishing somatic mutations in immunoglobulin genes, we analysed the mutation spectrum of somatically mutated immunoglobulin genes in B cells from PCNA K164R knock-in mice. A 10-fold reduction in A/T mutations is associated with a compensatory increase in G/C mutations—a phenotype similar to Polη and mismatch repair-deficient B cells. Mismatch recognition, PCNA-Ub and Polη probably act within one pathway to establish the majority of mutations at template A/T. Equally relevant, the G/C mutator(s) seems largely independent of PCNA K164 modification.

scholarly journals MicroRNA-96 Regulates Apoptosis by Targeting PDCD4 in Human Glioma Cells

2016 ◽  
Vol 16 (1) ◽  
pp. 92-98 ◽  
Author(s):  
Qing-qing Ma ◽  
Jian-ting Huang ◽  
Yun-gang Xiong ◽  
Xiao-yan Yang ◽  
Ran Han ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Critical Role ◽  
Glioma Cells ◽  
Primary Brain Tumor ◽  
Human Glioma Cells ◽  
Dismal Prognosis ◽  
Normal Human ◽  
Human Brains

Glioblastoma multiforme, the most common and aggressive form of primary brain tumor, presents a dismal prognosis. MicroRNAs play a critical role in the initiation, progression, and metastasis of cancer; however, the potential biological role of miRNAs in glioblastoma multiforme remains largely unknown. In our study, we found that microRNA-96 is upregulated in glioma tissues than in normal human brains. Transfection of microRNA-96 mimics into glioma cells significantly decreases apoptosis by suppressing PDCD4, a well-known tumor suppressor that is involved in apoptosis. In contrast, knockdown of microRNA-96 enhanced apoptosis. In vivo, microRNA-96 overexpression inhibits the apoptosis and increases tumor growth. These data suggest that microRNA-96 is a potential molecular target for glioma treatment.

scholarly journals Simultaneous Disruption of Two DNA Polymerases, Polη and Polζ, in Avian DT40 Cells Unmasks the Role of Polη in Cellular Response to Various DNA Lesions

PLoS Genetics ◽  
2010 ◽  
Vol 6 (10) ◽  
pp. e1001151 ◽  
Author(s):  
Kouji Hirota ◽  
Eiichiro Sonoda ◽  
Takuo Kawamoto ◽  
Akira Motegi ◽  
Chikahide Masutani ◽  
...  
Keyword(s):  
Cellular Response ◽  
Dna Polymerases ◽  
Dna Lesions ◽  
Dt40 Cells

scholarly journals Efficient and Error-Free Replication Past a Minor-Groove DNA Adduct by the Sequential Action of Human DNA Polymerases ι and κ

2004 ◽  
Vol 24 (13) ◽  
pp. 5687-5693 ◽  
Author(s):  
M. Todd Washington ◽  
Irina G. Minko ◽  
Robert E. Johnson ◽  
William T. Wolfle ◽  
Thomas M. Harris ◽  
...  
Keyword(s):  
Dna Adducts ◽  
Dna Polymerases ◽  
Minor Groove ◽  
Dna Lesions ◽  
Initial Reaction ◽  
Dna Minor Groove ◽  
Nucleotide Incorporation ◽  
A Minor ◽  
Y Family

ABSTRACT DNA polymerase ι (Polι) is a member of the Y family of DNA polymerases, which promote replication through DNA lesions. The role of Polι in lesion bypass, however, has remained unclear. Polι is highly unusual in that it incorporates nucleotides opposite different template bases with very different efficiencies and fidelities. Since interactions of DNA polymerases with the DNA minor groove provide for the nearly equivalent efficiencies and fidelities of nucleotide incorporation opposite each of the four template bases, we considered the possibility that Polι differs from other DNA polymerases in not being as sensitive to distortions of the minor groove at the site of the incipient base pair and that this enables it to incorporate nucleotides opposite highly distorting minor-groove DNA adducts. To check the validity of this idea, we examined whether Polι could incorporate nucleotides opposite the γ-HOPdG adduct, which is formed from an initial reaction of acrolein with the N2 of guanine. We show here that Polι incorporates a C opposite this adduct with nearly the same efficiency as it does opposite a nonadducted template G residue. The subsequent extension step, however, is performed by Polκ, which efficiently extends from the C incorporated opposite the adduct. Based upon these observations, we suggest that an important biological role of Polι and Polκ is to act sequentially to carry out the efficient and accurate bypass of highly distorting minor-groove DNA adducts of the purine bases.

scholarly journals Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Vilas Desai ◽  
Alok Bhushan
Keyword(s):  
Drug Delivery ◽  
Glioblastoma Multiforme ◽  
Effective Treatment ◽  
Standard Of Care ◽  
Natural Compounds ◽  
Epidemiological Studies ◽  
Chemotherapeutic Agents ◽  
Normal Brain ◽  
Current Standard

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.

scholarly journals Non-bulky Lesions in Human DNA: The Ways of Formation, Repair, and Replication

Acta Naturae ◽  
2017 ◽  
Vol 9 (3) ◽  
pp. 12-26 ◽  
Author(s):  
А. V. Ignatov ◽  
K. A. Bondarenko ◽  
A. V. Makarova
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
High Efficiency ◽  
Dna Polymerases ◽  
Dna Lesions ◽  
Translesion Dna Synthesis ◽  
Human Dna ◽  
Mechanisms Of Formation ◽  
Bulky Dna Lesions

DNA damage is a major cause of replication interruption, mutations, and cell death. DNA damage is removed by several types of repair processes. The involvement of specialized DNA polymerases in replication provides an important mechanism that helps tolerate persistent DNA damage. Specialized DNA polymerases incorporate nucleotides opposite lesions with high efficiency but demonstrate low accuracy of DNA synthesis. In this review, we summarize the types and mechanisms of formation and repair of non-bulky DNA lesions, and we provide an overview of the role of specialized DNA polymerases in translesion DNA synthesis.

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