• temozolomide
  • VANCOUVER, British Columbia and MENLO PARK, Calif., May 8, 2017 /PRNewswire/ -- DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on developing new cancer therapies, today announced new mechanism of action (MOA) data for its anti-cancer product candidate, VAL-083 (dianhydrogalactitol) , a "first-in-class" small-molecule DNA-targeting agent in temozolomide (Temodar™)-resistant GBM, at the World Federation of Neuro-Oncology Societies (WFNOS). (delmarpharma.com)
  • The effect of NSC-666715 on the cytotoxicity of the DNA-alkylating drug temozolomide (TMZ) to colon cancer cells was determined by in vitro clonogenic and in vivo xenograft assays. (aacrjournals.org)
  • EMS mutagenesis Temozolomide 6-O-Methylguanine at Sigma-Aldrich Fahrer J, Kaina B (2013). (wikipedia.org)
  • The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. (aacrjournals.org)
  • Augmented HR repair is a novel mechanism underlying acquired temozolomide resistance in GBM, and this raises the possibility of improving the therapeutic response to temozolomide by targeting HR with small-molecule inhibitors of CDK1/2. (aacrjournals.org)
  • The current standard of care is surgical resection coupled with ionizing radiation (IR) and the chemotherapeutic agent temozolomide (Temodar ® , Temodal ® , TMZ) [ 6 , 7 ]. (mdpi.com)
  • genes
  • Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection. (wikipedia.org)
  • While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumour heterogeneity. (wikipedia.org)
  • We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. (aacrjournals.org)
  • We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. (aacrjournals.org)
  • Twenty-two DNA repair genes with hypermethylated promoters, and reduced or absent expression, were found to occur among 17 types of cancer, as listed in two review articles. (wikipedia.org)
  • Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes. (wikipedia.org)
  • Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. (wikipedia.org)
  • genome
  • O6-methylguanine DNA methyltransferase is crucial for genome stability. (wikipedia.org)
  • DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. (wikipedia.org)
  • Encoded by eukaryotic nuclear DNA in plants and animals and by viral DNA in certain viruses whose genome is based on DNA, miRNAs function via base-pairing with complementary sequences within mRNA molecules. (wikipedia.org)
  • either "global genome" NER or "transcription-coupled" NER) acts on a variety of helix-distorting DNA lesions, such as the pyrimidine dimers caused by UV light, and chemical adducts, such as those caused by benzo( a )pyrene ( 5 ). (aacrjournals.org)
  • A high frequency of externally caused DNA damage can be one source of genome instability since DNA damages can cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation. (wikipedia.org)
  • Because endogenous (metabolically-caused) DNA damage is very frequent, occurring on average more than 60,000 times a day in the genomes of human cells, any reduced DNA repair is likely an important source of genome instability. (wikipedia.org)
  • There are hotspots in the genome where DNA sequences are prone to gaps and breaks after inhibition of DNA synthesis such as in the aforementioned checkpoint arrest. (wikipedia.org)
  • polymerase
  • In the present study, we used structure-based molecular docking of DNA polymerase β (Pol-β) and identified a potent small molecular weight inhibitor, NSC-666715. (aacrjournals.org)
  • It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. (ebi.ac.uk)
  • We found that, unlike wildtype, the dnaE486 (alpha catalytic subunit of DNA polymerase III holoenzyme) mutant, and a DnaX (clamp loader subunits) over-producer, are sensitive to cisplatin but resistant to MNNG at the permissive temperature for growth. (pubmedcentralcanada.ca)
  • Resynthesis is accomplished by the polymerase III holoenzyme complex and the resulting nick is ligated by DNA ligase [ 16 ]. (pubmedcentralcanada.ca)
  • induce
  • In cancer cell-lines VAL-083 is able to induce DNA damage and resultant cell apoptosis even when MMR enzymes (MLH-1 and MSH-2) are made constitutively active. (delmarpharma.com)
  • In contrast, animal miRNAs are able to recognize their target mRNAs by using as little as 6-8 nucleotides (the seed region) at the 5' end of the miRNA, which is not enough pairing to induce cleavage of the target mRNAs. (wikipedia.org)
  • cancers
  • Thus, the interference with DNA repair has emerged as an important approach to combination therapy against such cancers ( 7 ). (aacrjournals.org)
  • A common carcinogenic alteration, found in many cancers and in their adjacent field defects from which the cancers likely arose, is reduced expression of one or more DNA repair enzymes. (wikipedia.org)
  • The article Werner syndrome ATP-dependent helicase indicates the DNA repair gene WRN has a promoter that is frequently hypermethylated in a number of cancers, with hypermethylation occurring in 11% to 38% of colorectal, head and neck, stomach, prostate, breast, thyroid, non-Hodgkin lymphoma, chondrosarcoma and osteosarcoma cancers (see WRN). (wikipedia.org)
  • ligase
  • We determined the specificity of this small molecular weight inhibitor for Pol-β by using in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single-nucleotide and long-patch BER. (aacrjournals.org)
  • It blocked Pol-β-directed single-nucleotide and long-patch BER without affecting the activity of APE1, Fen1, and DNA ligase I. Fluorescence anisotropy data suggested that NSC-666715 directly and specifically interacts with Pol-β and interferes with binding to damaged DNA. (aacrjournals.org)
  • primarily
  • In addition to these, a less explored but critical area of cancer chemotherapy is blocking the ability of cancer cells to recognize and repair the damaged DNA, which primarily results from the use of chemotherapeutic drugs, including DNA-alkylating drugs ( 5 , 6 ). (aacrjournals.org)
  • expression
  • Since reduced DNA repair expression is often present in a field cancerization or a field defect, it is likely to have been an early step in progression to the cancer. (wikipedia.org)
  • Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants. (wikipedia.org)
  • pathways
  • Like many of the other DNA repair pathways in human cells, the processing of such breaks involves a series of coordinated, sequential reactions in which the damage is detected and processed and any gaps generated are filled and religated. (aacrjournals.org)
  • 6 Both of these pathways follow the adenomacarcinoma sequence. (scielo.org.za)
  • damage
  • The balance between DNA damage and repair determines the final therapeutic consequences of these drugs. (aacrjournals.org)
  • Carboxymethylating agents are potential sources of endogenous DNA damage that have been proposed as possible contributors to gastrointestinal carcinogenesis. (sussex.ac.uk)
  • In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. (wikipedia.org)
  • Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. (wikipedia.org)
  • As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. (wikipedia.org)
  • DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. (wikipedia.org)
  • Monoadduct damage cause by change in single nitrogenous base of DNA Diadduct damage Damage caused by exogenous agents comes in many forms. (wikipedia.org)
  • Finally, direct reversal of DNA damage, an unusual form of DNA repair, is also present in human cells. (aacrjournals.org)
  • In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy. (mdpi.com)
  • In addition, however, recombinational repair mechanisms are as important as NER in allowing cells to survive cisplatin damage since E. coli strains in which recombination is defective show increased susceptibility to cisplatin [ 11 , 12 ]. (pubmedcentralcanada.ca)
  • Catalytic Inhibitors of Topoisomerase II Are DNA-Damaging Agents: Induction of Chromosomal Damage by Merbarone and ICRF-187, Environmental and Molecular Mutagenesis, vol. 39, pp. 348-356 (2002). (freepatentsonline.com)
  • DNA damage is considered to be the primary cause of cancer. (wikipedia.org)
  • As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. (wikipedia.org)
  • In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer. (wikipedia.org)
  • In addition to S-phase checkpoints, G1 and G2 checkpoints exist to check for transient DNA damage which could be caused by mutagens such as UV damage. (wikipedia.org)
  • An example is the Saccharomyces pombe gene rad9 which arrests the cells in late S/G2 phase in the presence of DNA damage caused by radiation. (wikipedia.org)
  • defects
  • The results further suggest that the disruption of BER by NSC-666715 negates its contribution to drug resistance and bypasses other resistance factors, such as mismatch repair defects. (aacrjournals.org)
  • Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. (aacrjournals.org)
  • vivo
  • The biologically inactive trans isomer of cisplatin also produces 1,3-GNG adducts, interstrand crosslinks and monoadducts [ 4 , 5 ], suggesting that intrastrand crosslinks between adjacent purines are the biologically important adducts of cisplatin since they efficiently block progression of DNA polymerases in vitro and in vivo [ 6 ]. (pubmedcentralcanada.ca)
  • cells
  • In many cases, an elevated DNA repair capacity in tumor cells leads to drug resistance and severely limits the efficacy of DNA-alkylating drugs. (aacrjournals.org)
  • The cytotoxicity of the model DNA carboxymethylating agent azaserine was investigated in human cells. (sussex.ac.uk)
  • Cells must also cope with the presence of DNA single-strand and double-strand breaks (SSB and DSB). (aacrjournals.org)
  • In wildtype cells, mismatch correction is restricted to the hemimethylated region as MutH has little, if any, activity on fully methylated DNA [ 17 ]. (pubmedcentralcanada.ca)
  • In cancer cells "global hypomethylation" due to disruption in DNA methyltransferases (DNMTs) may promote mitotic recombination and chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis. (wikipedia.org)
  • The cells that arrested were able to survive due to the increased time in S/G2 phase allowing for DNA repair enzymes to function fully. (wikipedia.org)
  • excision
  • As a result of only modest improvements in survival emerging from the traditional triad of surgical excision, radiotherapy, and chemotherapy, there have been intensified research efforts studying immunotherapy as a more effective treatment paradigm [ 6 , 15 , 16 ]. (mdpi.com)
  • These lesions are usually removed either directly, in the first case by a methyltransferase, or through base excision repair using specific glycosylases. (pubmedcentralcanada.ca)
  • cell
  • The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. (wikipedia.org)
  • Carcinomas occur when the DNA of a cell is damaged or altered and the cell begins to grow uncontrollably and become malignant. (wikipedia.org)
  • thymine
  • It base-pairs to thymine rather than cytosine, causing a G:C to A:T transition in DNA. (wikipedia.org)
  • O 6 -meG can then mispair again with thymine leading to repeated cycles of MMR attempts and persistent single-stranded gaps in DNA ( 18 ). (aacrjournals.org)
  • survival
  • 10% 5-year survival rate [ 3 , 6 ]. (mdpi.com)
  • However, this treatment only provides GBM patients with a 12-14 month survival period post-diagnosis [ 6 , 7 ]. (mdpi.com)
  • progression
  • As discussed by Jin and Roberston in their review, silencing of a DNA repair gene by hypermethylation may be a very early step in progression to cancer. (wikipedia.org)