alkylating agents


Summary: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.

Top Publications

  1. pmc Balancing repair and tolerance of DNA damage caused by alkylating agents
    Dragony Fu
    Department of Biological Engineering, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Rev Cancer 12:104-20. 2012
  2. pmc Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction
    Amy M Furda
    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    DNA Repair (Amst) 11:684-92. 2012
  3. pmc Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks
    Cecilia Lundin
    Department of Genetics, Microbiology and Toxicology, Stockholm University Svante Arrhenius väg 16, S 106 91 Stockholm, Sweden
    Nucleic Acids Res 33:3799-811. 2005
  4. ncbi Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death
    Ling Ya Chiu
    Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
    Biochem Pharmacol 81:459-70. 2011
  5. ncbi Mutagenic damage to mammalian cells by therapeutic alkylating agents
    B J Sanderson
    School of Medicine, Flinders University of South Australia, Adelaide, Australia
    Mutat Res 355:41-57. 1996
  6. pmc Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice
    Lisiane B Meira
    Department of Biological Engineering and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Proc Natl Acad Sci U S A 106:888-93. 2009
  7. ncbi O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy
    Geoffrey P Margison
    CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK
    Bioessays 24:255-66. 2002
  8. ncbi Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures
    Filippo Doria
    Dipartimento di Chimica, Universita di Pavia, V le Taramelli 10, 27100 Pavia, Italy
    Org Biomol Chem 10:2798-806. 2012
  9. pmc Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair
    Dana A Löser
    Genome Damage and Stability Centre, University of Sussex, Falmer, United Kingdom
    Mol Cancer Ther 9:1775-87. 2010
  10. ncbi Molecular cloning of a gene which regulates the adaptive response to alkylating agents in Escherichia coli
    B Sedgwick
    Mol Gen Genet 191:466-72. 1983

Detail Information

Publications226 found, 100 shown here

  1. pmc Balancing repair and tolerance of DNA damage caused by alkylating agents
    Dragony Fu
    Department of Biological Engineering, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Rev Cancer 12:104-20. 2012
    b>Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage...
  2. pmc Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction
    Amy M Furda
    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    DNA Repair (Amst) 11:684-92. 2012
    ..These results suggest that persistent mtDNA damage is not sufficient to cause mitochondrial dysfunction...
  3. pmc Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks
    Cecilia Lundin
    Department of Genetics, Microbiology and Toxicology, Stockholm University Svante Arrhenius väg 16, S 106 91 Stockholm, Sweden
    Nucleic Acids Res 33:3799-811. 2005
    ..We speculate that the reason for recombination-deficient cells being sensitive to MMS is due to the role of HR in repair of MMS-induced stalled replication forks, rather than for repair of cellular DSBs or heat-labile damage...
  4. ncbi Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death
    Ling Ya Chiu
    Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
    Biochem Pharmacol 81:459-70. 2011
    ..Moreover, intracellular calcium elevation and ROS production have mutual amplification effects and thus contribute to PARP-1-mediated parthanatos...
  5. ncbi Mutagenic damage to mammalian cells by therapeutic alkylating agents
    B J Sanderson
    School of Medicine, Flinders University of South Australia, Adelaide, Australia
    Mutat Res 355:41-57. 1996
    Cytotoxic alkylating agents used as therapeutics include nitrogen mustards, ethyleneimines, alkyl sulfonates, nitrosoureas and triazenes. Their reactivity with DNA, RNA and proteins can cause cell death...
  6. pmc Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice
    Lisiane B Meira
    Department of Biological Engineering and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Proc Natl Acad Sci U S A 106:888-93. 2009
    ..In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration...
  7. ncbi O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy
    Geoffrey P Margison
    CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK
    Bioessays 24:255-66. 2002
    ..They are generated by certain classes of carcinogenic and chemotherapeutic alkylating agents. There is consequently a great deal of interest in this repair system in relation to both carcinogenesis and ..
  8. ncbi Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures
    Filippo Doria
    Dipartimento di Chimica, Universita di Pavia, V le Taramelli 10, 27100 Pavia, Italy
    Org Biomol Chem 10:2798-806. 2012
    ..These findings points to our hybrid ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies...
  9. pmc Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair
    Dana A Löser
    Genome Damage and Stability Centre, University of Sussex, Falmer, United Kingdom
    Mol Cancer Ther 9:1775-87. 2010
    ..PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues...
  10. ncbi Molecular cloning of a gene which regulates the adaptive response to alkylating agents in Escherichia coli
    B Sedgwick
    Mol Gen Genet 191:466-72. 1983
    The ada+ gene of E. coli is a regulatory gene of the adaptive response to simple alkylating agents. ada mutants are sensitive to both the mutagenicity and toxicity of alkylating agents, and are unable to induce O6-methylguanine DNA ..
  11. pmc Alkylating DNA damage stimulates a regulated form of necrotic cell death
    Wei Xing Zong
    Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 18:1272-82. 2004
  12. ncbi Alkylation damage in DNA and RNA--repair mechanisms and medical significance
    Finn Drabløs
    Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N 7489 Trondheim, Norway
    DNA Repair (Amst) 3:1389-407. 2004
    ..of the MMR system in an AGT-defective background causes resistance to the killing effects of O(6)-alkylating agents, but not to the mutagenic effect...
  13. ncbi Do dose response thresholds exist for genotoxic alkylating agents?
    G J S Jenkins
    Swansea School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP and School of Biological Sciences, University of Wales, Swansea, UK
    Mutagenesis 20:389-98. 2005
    ..the potential mechanisms involved in such thresholded responses, particularly in relation to those of alkylating agents. As alkylating agents are representative model DNA reactive compounds with well characterized activities and ..
  14. pmc Role of Dot1 in the response to alkylating DNA damage in Saccharomyces cerevisiae: regulation of DNA damage tolerance by the error-prone polymerases Polzeta/Rev1
    Francisco Conde
    Instituto de Microbiologia Bioquimica, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain
    Genetics 179:1197-210. 2008
    ..We propose that Dot1 inhibits translesion synthesis (TLS) by Polzeta/Rev1 and that the MMS resistance observed in the dot1 mutant results from the enhanced TLS activity...
  15. ncbi Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction
    Giulia Cipriani
    Department of Pharmacology, University of Florence, 50139 Florence, Italy
    J Biol Chem 280:17227-34. 2005
    ..Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death...
  16. ncbi Regulation of tolerance to DNA alkylating damage by Dot1 and Rad53 in Saccharomyces cerevisiae
    Francisco Conde
    Instituto de Microbiologia Bioquimica, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain
    DNA Repair (Amst) 9:1038-49. 2010
    ..We propose that threshold levels of Rad53 activity exquisitely modulate the tolerance to alkylating damage at least by controlling the abundance of the key TLS factor Rev1 bound to chromatin...
  17. ncbi Microarray expression analysis of the early N-methy-N-nitrosourea-induced retinal degeneration in rat
    Liu Yang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou 510060, PR China
    Neurosci Lett 418:38-43. 2007
    ..These microarray results provide clues to understand the molecular pathways underlying photoreceptor degeneration and indicate directions for future studies...
  18. ncbi Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine
    Geoffrey P Margison
    Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 4BX, UK
    Mutagenesis 17:483-7. 2002
    b>Alkylating agents are a structurally diverse group of compounds that cause a wide range of biological effects, including cell death, mutation and cancer...
  19. pmc Mycothiol-deficient Mycobacterium smegmatis mutants are hypersensitive to alkylating agents, free radicals, and antibiotics
    Mamta Rawat
    Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia V5Z 3J5, Canada
    Antimicrob Agents Chemother 46:3348-55. 2002
    ..analysis revealed that these MSH-deficient mutants possess increased susceptibilities to free radicals and alkylating agents and to a wide range of antibiotics including erythromycin, azithromycin, vancomycin, penicillin G, rifamycin,..
  20. ncbi Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint
    J A Tercero
    Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms EN6 3LD, UK
    Nature 412:553-7. 2001
    ..Thus, preventing damage-induced DNA replication fork catastrophe seems to be a primary mechanism by which checkpoints preserve viability in the face of DNA alkylation...
  21. ncbi Influence of orange juice over the genotoxicity induced by alkylating agents: an in vivo analysis
    Silvia Isabel Rech Franke
    Curso de Nutricao, Departamento de Educação Física e Saúde, Universidade de Santa Cruz do Sul UNISC, Santa Cruz do Sul, RS, Brazil
    Mutagenesis 20:279-83. 2005
    ..Methyl methanesulfonate (MMS) and cyclophosphamide (CP) are alkylating agents that differ in their mode of action...
  22. pmc Genomic predictors of interindividual differences in response to DNA damaging agents
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Genes Dev 22:2621-6. 2008
    ..Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis...
  23. ncbi Transient adenoviral N-methylpurine DNA glycosylase overexpression imparts chemotherapeutic sensitivity to human breast cancer cells
    Mikael Rinne
    Herman B Wells Center for Pediatric Research, 1044 West Walnut, Building R4, Room 302C, Indianapolis, IN 46202, USA
    Mol Cancer Ther 3:955-67. 2004
    ..cancer cells to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results show that MPG-overexpressing cells are significantly more sensitive to the alkylating agents ..
  24. ncbi 3-Methyladenine DNA glycosylase-deficient Aag null mice display unexpected bone marrow alkylation resistance
    Richard B Roth
    Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    Cancer Res 62:656-60. 2002 3-methyladenine (3MeA) DNA glycosylase become sensitive to the lethal and clastogenic effects of alkylating agents. Surprisingly, myeloid progenitor bone marrow (BM) cells derived from Aag -/- mice were more resistant than ..
  25. pmc DNA repair modulates the vulnerability of the developing brain to alkylating agents
    G E Kisby
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR 97239, United States
    DNA Repair (Amst) 8:400-12. 2009
    ..the methylating agents methylazoxymethanol (MAM) and dimethyl sulfate (DMS) and the mono- and bifunctional alkylating agents chloroethylamine (CEA) and nitrogen mustard (HN2), in granule cell neurons derived from the cerebellum of ..
  26. pmc Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor
    Vladimir V Kalinichenko
    University of Illinois at Chicago, College of Medicine, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60607, USA
    Genes Dev 18:830-50. 2004
    ..Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors...
  27. ncbi Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1
    Valerie Schreiber
    UPR 9003 du Centre National de la Recherche Scientifique, Laboratoire conventionné avec le Commissariat à l Energie Atomique, Universite Louis Pasteur, Ecole Superieure de Biotechnologie de Strasbourg, Illkirch, France
    J Biol Chem 277:23028-36. 2002
  28. pmc Methylation-induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1
    Petr Cejka
    Institute of Molecular Cancer Research, University of Zurich, August Forel Strasse 7, CH 8008 Zürich Switzerland
    EMBO J 22:2245-54. 2003
  29. ncbi The intracellular signal for induction of resistance to alkylating agents in E. coli
    I Teo
    Cell 45:315-24. 1986
    ..This is apparently the first example of conversion of a regulatory gene product to a transcriptional activator by a posttranslational modification event...
  30. pmc Gene expression analysis of tumor spheroids reveals a role for suppressed DNA mismatch repair in multicellular resistance to alkylating agents
    Giulio Francia
    Molecular and Cellular Biology Research, Sunnybrook and Women s College Health Sciences Centre, S 217 Research Building, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5
    Mol Cell Biol 24:6837-49. 2004
    ..Analysis of EMT-6 tumor variants selected in vivo for acquired resistance to alkylating agents identified eight genes whose expression correlated with drug resistance in tumor spheroids...
  31. pmc Preferential DNA damage prevention by the E. coli AidB gene: A new mechanism for the protection of specific genes
    Valentina Rippa
    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA
    DNA Repair (Amst) 10:934-41. 2011
    aidB is one of the four genes of E. coli that is induced by alkylating agents and regulated by Ada protein. Three genes (ada, alkA, and alkB) encode DNA repair proteins that remove or repair alkylated bases...
  32. pmc Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis
    Rana S Moubarak
    Apoptose et Systeme Immunitaire, CNRS URA 1961, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France
    Mol Cell Biol 27:4844-62. 2007
    ..Our data shed new light on the mechanisms regulating AIF-dependent necrosis and support the notion that, like apoptosis, necrosis could be a highly regulated cell death program...
  33. pmc Repair of DNA strand breaks by the overlapping functions of lesion-specific and non-lesion-specific DNA 3' phosphatases
    J R Vance
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 0602, USA
    Mol Cell Biol 21:7191-8. 2001
    ..Taken together, these results demonstrate a clear role for the lesion-specific enzyme, Tpp1, in the repair of a subset of DNA strand breaks...
  34. ncbi Repair of alkylated DNA: recent advances
    Barbara Sedgwick
    Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK
    DNA Repair (Amst) 6:429-42. 2007
    Cytotoxic and mutagenic methylated bases in DNA can be generated by endogenous and environmental alkylating agents. Such damaged bases are removed by three distinct strategies...
  35. ncbi Ligand association with the rabbit kidney and brain Y1, Y2 and Y5-like neuropeptide Y (NPY) receptors shows large subtype-related differences in sensitivity to chaotropic and alkylating agents
    S L Parker
    Department of Pharmacology, University of Tennessee College of Medicine, Memphis 38163, USA
    Regul Pept 87:59-72. 2000
    ..The Y2 sites resistant to guanosine polyphosphates and restricted-access alkylators were detected mainly in particulates slowly solubilized by cholate at 0-5 degrees C; these sites could be clustered...
  36. ncbi Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development
    H D Beall
    Department of Pharmaceutical Sciences, School of Pharmacy, The University of Montana, Missoula, MT 59812, USA
    Front Biosci 5:D639-48. 2000
    b>Alkylating agents have been used to treat cancer since the 1940s. Quinone-containing alkylating agents represent a class of drugs called "bioreductive alkylating agents...
  37. ncbi Increased sensitivity of transforming growth factor (TGF) beta 1 null cells to alkylating agents reveals a novel link between TGFbeta signaling and O(6)-methylguanine methyltransferase promoter hypermethylation
    H Yamada
    Toxicology Laboratory, Pharmaceutical Research Laboratories, Taisho Pharmaceuticals, Tokyo 170-8633, Japan
    J Biol Chem 276:19052-8. 2001
    ..that nonneoplastic TGFbeta1-/- keratinocyte cell lines exhibit increased sensitivity to cell killing by alkylating agents, and this is due to lack of expression of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (..
  38. pmc Monoalkyl sulfates as alkylating agents in water, alkylsulfatase rate enhancements, and the "energy-rich" nature of sulfate half-esters
    Richard Wolfenden
    Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 104:83-6. 2007
    ..esters, coupled with their marked resistance to hydrolysis, renders them capable of acting as sulfating or alkylating agents under relatively mild conditions...
  39. ncbi Alkylating agents and DNA polymerases
    Leon P Bignold
    Institute of Medical and Veterinary Science, Adelaide, SA 5001, Australia
    Anticancer Res 26:1327-36. 2006
    b>Alkylating agents, for example nitrogen "mustards", are variably toxic, mutagenic, carcinogenic and teratogenic, but by mechanisms which have not been clearly established...
  40. pmc Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis
    L Rajkumar
    Department of Molecular and Cell Biology and The Cancer Research Laboratory, University of California, 491 Life Sciences Addition, Berkeley, CA 94720, USA
    Proc Natl Acad Sci U S A 98:11755-9. 2001
  41. ncbi AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents
    Jing Zhou
    Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore
    FEBS Lett 587:170-7. 2013
    ..Taken together, data from this study reveal a novel mechanism in controlling MNNG-mediated autophagy via AMPK activation downstream of PARP-1 activation and ATP depletion...
  42. ncbi The metabolism of quinone-containing alkylating agents: free radical production and measurement
    P L Gutierrez
    The University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, 655 W Baltimore Street, Baltimore, MD 21201, USA
    Front Biosci 5:D629-38. 2000
    ..In this particular review we are interested in describing the phenomenon of redox-cycling, how it is measured, and the biological consequences of the presence of the semiquinone and the oxygen radicals generated...
  43. ncbi Distamycin A as stem of DNA minor groove alkylating agents
    Pier Giovanni Baraldi
    Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortara 17 19, I 44100 Ferrara, Italy
    Curr Top Med Chem 4:231-9. 2004
    ..Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article...
  44. ncbi Detection of localized retinal malfunction in retinal degeneration model using a multielectrode array system
    Kohei Homma
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Chou ku, Kobe, Japan
    J Neurosci Res 87:2175-82. 2009
    ..This spatial information should be valuable in investigating local functional recovery in therapeutically treated areas, such as in gene transfer or cell transplantation...
  45. ncbi Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials
    Airo Tsubura
    Department of Pathology II, Kansai Medical University, Moriguchi, Osaka 570 8506, Japan
    In Vivo 25:11-22. 2011
    ..In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models...
  46. ncbi Downregulation of MDM2 stabilizes p53 by inhibiting p53 ubiquitination in response to specific alkylating agents
    T Inoue
    Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA
    FEBS Lett 490:196-201. 2001
    ..In this report, the DNA alkylating agents mitomycin C (MMC) and methylmethane sulfonate (MMS), as well as UV radiation, stabilized p53 in a manner ..
  47. pmc A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents
    Shoji Hata
    Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1 5 45 Yushima, Bunkyo ku, Tokyo 113 8510, Japan
    J Biol Chem 287:22089-98. 2012
    ..the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP ..
  48. ncbi Oxidation of methylhydrazines to mutagenic methylating derivatives and inducers of the adaptive response of Escherichia coli to alkylation damage
    B Sedgwick
    Imperial Cancer Research Fund, Clare Hall Laboratories, Potters Bar, Hertfordshire, England
    Cancer Res 52:3693-7. 1992
    ..These observations support the suggestion that metabolic oxidation of methylhydrazines in mammalian systems may be required to generate the mutagenic/carcinogenic derivatives...
  49. pmc CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents
    D L Boger
    Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 92:3642-9. 1995
    ..For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined...
  50. ncbi Role of nucleotide- and base-excision repair in genotoxin-induced neuronal cell death
    G E Kisby
    Center for Research on Occupational and Environmental Toxicology CROET, Oregon Health Sciences University, Portland, OR 97239, USA
    DNA Repair (Amst) 3:617-27. 2004
    ..These studies demonstrate that BER and NER are required to protect neurons from genotoxin-induced cell death...
  51. ncbi DNA minor groove alkylating agents
    W A Denny
    Auckland Cancer Society Research Centre, School of Biomedical and Health Sciences, The University of Auckland, Auckland, Private Bag 92109, New Zealand
    Curr Med Chem 8:533-44. 2001
    ..Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed...
  52. ncbi Amino acid nitrosation products as alkylating agents
    M del P García-Santos
    Departamento de Quimica Fisica, Universidad de Salamanca, E 37008 Salamanca, Spain
    J Am Chem Soc 123:7506-10. 2001
    Nitrosation reactions of alpha-, beta-, and gamma-amino acids whose reaction products can act as alkylating agents of DNA were investigated...
  53. ncbi Molecular mechanisms of adaptive response to alkylating agents in Escherichia coli and some remarks on O(6)-methylguanine DNA-methyltransferase in other organisms
    Karol Kleibl
    Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava 37, Slovak Republic
    Mutat Res 512:67-84. 2002
    b>Alkylating agents are environmental genotoxic agents with mutagenic and carcinogenic potential, however, their properties are also exploited in the treatment of malignant diseases...
  54. ncbi Validation of a chemical osteoarthritis model in rabbit temporomandibular joint: a compliment to biomechanical models
    G Cledes
    Laboratoire de Biomatériaux et Biomécanique ostéo articulaire, UMR CNRS 7052, 10, avenue de Verdun 75010, Paris, France
    Int J Oral Maxillofac Surg 35:1026-33. 2006
    ..This could be interpreted as a repairing attempt due to the specific potential of fibrocartilage proliferative cells...
  55. ncbi Evidence-based mini-review: the role of alkylating agents in the initial treatment of chronic lymphocytic leukemia patients with the 11q deletion
    Wei Ding
    Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
    Hematology Am Soc Hematol Educ Program 2010:90-2. 2010
    ..Fluorescence in situ hybridization (FISH) analysis revealed del(11q22.3), but negative for t(11:14). What should be used to treat his chronic lymphocytic leukemia (CLL) disease?..
  56. ncbi Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage
    Xuesong Liu
    Department R47S, Cancer Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA
    Cancer Biol Ther 7:934-41. 2008
    ..Unlike in HeLa cells, ABT-888 protected MNNG induced cell death in normal human fibroblasts. Our study provides evidence that PARP activity determines the fate of HeLa cells by regulating the level of ATP after treatment with MNNG...
  57. ncbi The biological effects of N3-methyladenine
    Gilberto Fronza
    Mutagenesis Laboratory, National Cancer Research Institute IST, L go R Benzi, 10, 16132 Genova, Italy
    J Cell Biochem 91:250-7. 2004
    ..One of the serious side effects of alkylating agents is that they create both toxic (desired) and mutagenic (undesired) lesions...
  58. ncbi The effect of folate deficiency on the hprt mutational spectrum in Chinese hamster ovary cells treated with monofunctional alkylating agents
    R F Branda
    Department of Medicine and the Vermont Cancer Center, University of Vermont, Burlington, VT 05405, USA
    Mutat Res 427:79-87. 1999
    Folic acid deficiency acts synergistically with alkylating agents to increase DNA strand breaks and mutant frequency at the hprt locus in Chinese hamster ovary (CHO) cells...
  59. pmc Repair of cyclobutane pyrimidine dimers or dimethylsulfate damage in DNA is identical in normal or telomerase-immortalized human skin fibroblasts
    Steven E Bates
    Department of Biology, Beckman Research Institute, City of Hope National Medical Center 1450 East Duarte Road, Duarte, CA 91010, USA
    Nucleic Acids Res 33:2475-85. 2005
    ..Thus, telomerase expression and consequent immortalization of skin fibroblasts do not alter nucleotide or base excision repair in human cells...
  60. ncbi Mispair-aligned N3T-alkyl-N3T interstrand cross-linked DNA: synthesis and characterization of duplexes with interstrand cross-links of variable lengths
    Christopher J Wilds
    Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA
    J Am Chem Soc 126:9257-65. 2004
    Therapeutic bifunctional alkylating agents generate interstrand cross-links in duplex DNA...
  61. ncbi A gene-driven ENU-based approach to generating an allelic series in any gene
    Mohamed Mohideen Quwailid
    MRC Mammalian Genetics Unit, Medical Research Council, OX11 0RD, Harwell, Oxfordshire, UK
    Mamm Genome 15:585-91. 2004
    ..It is now available to academic collaborators as a community resource...
  62. ncbi Quinone methides tethered to naphthalene diimides as selective G-quadruplex alkylating agents
    Marco Di Antonio
    Dipartimento di Scienze Farmaceutiche, Universita di Padova, Via Marzolo, 5, 35131 Padova, Italy
    J Am Chem Soc 131:13132-41. 2009
    ..bis-substituted naphthalene diimides were efficiently synthesized, and their reactivity as activatable bis-alkylating agents was investigated in the presence of thiols and amines in aqueous buffered solutions...
  63. ncbi Recent progress on the Ada response for inducible repair of DNA alkylation damage
    Barbara Sedgwick
    Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK
    Oncogene 21:8886-94. 2002
  64. ncbi The stroma as a crucial target in rat mammary gland carcinogenesis
    Maricel V Maffini
    Department of Anatomy and Cellular Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
    J Cell Sci 117:1495-502. 2004
    ..Our results suggest that the stroma is a crucial target of the carcinogen and that mutation in the Ha-ras-1 gene is neither necessary nor sufficient for tumor initiation...
  65. ncbi CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas
    Maria F Paz
    Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, Spain
    Clin Cancer Res 10:4933-8. 2004
    The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island...
  66. ncbi DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard
    T A Gourdie
    Cancer Research Laboratory, School of Medicine, University of Auckland, Private Bag, New Zealand
    J Med Chem 33:1177-86. 1990
    ..These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.
  67. ncbi DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents
    B J Glassner
    Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA
    Mutagenesis 14:339-47. 1999
    ..cells from Mgmt -/- mice were significantly more sensitive to the toxic effects of the chemotherapeutic alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin and temozolomide than those from Mgmt wild-type mice...
  68. pmc Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes
    H Kawate
    Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812 8582, Japan
    Proc Natl Acad Sci U S A 95:5116-20. 1998
    ..the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an ..
  69. ncbi DNA repair in mammalian cells: Direct DNA damage reversal: elegant solutions for nasty problems
    A P M Eker
    Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
    Cell Mol Life Sci 66:968-80. 2009
    ..Part of a Multi-author Review)...
  70. ncbi O6-alkylguanine-DNA alkyltransferase in cutaneous T-cell lymphoma: implications for treatment with alkylating agents
    M E Dolan
    Department of Medicine, University of Chicago, Illinois 60637, USA
    Clin Cancer Res 5:2059-64. 1999
    ..Because AGT is a primary means of cell resistance to alkylating agents, the low level of AGT in neoplastic T lymphocytes from patients with mycosis fungoides suggests that ..
  71. ncbi A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry
    Roberto Alzaga
    Pfizer Analytical Research Centre, Ghent University, Krijgslaan 281 S4 bis, B 9000 Ghent, Belgium
    J Pharm Biomed Anal 45:472-9. 2007
    A simple, reliable and fast procedure for the simultaneous determination of residues of some common alkylating agents (AAs), such as mesylates, besylates, tosylates and sulfates, employed in drug synthesis, has been developed by in situ ..
  72. pmc Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage
    El Bachir Affar
    Laboratory for Skin Cancer Research, Hospital Research Center of Laval University Centre Hospitalier Universitaire de Québec, Faculty of Medicine, Laval University, 2705, Laurier Boulevard, Room S16, Sainte Foy, Quebec, Canada
    Proc Natl Acad Sci U S A 99:245-50. 2002
    ..5-0.6 pH units may be a negative regulator of apoptosis while permitting necrotic death of cells with extensively damaged DNA...
  73. pmc Induction of specific Escherichia coli genes by sublethal treatments with alkylating agents
    M R Volkert
    Proc Natl Acad Sci U S A 81:4110-4. 1984
    Fusions of the lac operon to genes induced by treatment with sublethal levels of alkylating agents have been selected from random insertions of the Mu-dl(ApRlac) phage by screening for induction of beta-galactosidase activity in the ..
  74. ncbi Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents
    M Christmann
    Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D 55131 Mainz, Germany
    J Biol Chem 275:36256-62. 2000
    ..The finding that treatment of cells with O(6)-methylguanine-generating mutagens results in an increase of MutSalpha and GT binding activity in the nucleus indicates a novel type of genotoxic stress response...
  75. ncbi DNA interstrand crosslink formation by mechlorethamine at a cytosine-cytosine mismatch pair: kinetics and sequence dependence
    R M Romero
    Department of Pharmaceutical Sciences, University of Southern California, Los Angeles 90089-9121, USA
    Arch Biochem Biophys 386:143-53. 2001
  76. ncbi Detection of DNA damage derived from a direct acting ethylating agent present in cigarette smoke by use of liquid chromatography-tandem mass spectrometry
    Rajinder Singh
    Cancer Biomarkers and Prevention Group, Biocenter, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom
    Chem Res Toxicol 18:249-56. 2005
  77. pmc Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents
    Annamaria Biroccio
    Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Rome 00158, Italy
    Neoplasia 6:195-206. 2004
    ..By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental ..
  78. ncbi A genetic screen for mouse mutations with defects in serotonin responsiveness
    Karin C Weiss
    Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
    Brain Res Mol Brain Res 115:162-72. 2003
    ..Thus, it is well worth expanding on this genetic screen in its current form and by addition of further pharmacologic assays in the future...
  79. ncbi Alkyltransferase-like proteins
    Geoffrey P Margison
    Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom
    DNA Repair (Amst) 6:1222-8. 2007
    ..their mechanism of action and role in protecting the host organisms against the biological effects of O(6)-alkylating agents, and their evolution...
  80. ncbi Long-term follow-up of initial trabeculectomy with mitomycin C for primary open-angle glaucoma in Japanese patients
    Takashi Shigeeda
    Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo ku, Tokyo, Japan
    J Glaucoma 15:195-9. 2006
    ..To determine the long-term intraocular pressure (IOP) control and postoperative complications after initial trabeculectomy with use of mitomycin C (MMC) in patients with primary open-angle glaucoma (POAG)...
  81. ncbi Nicotinamide blocks N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in rats through poly (ADP-ribose) polymerase activity and Jun N-terminal kinase/activator protein-1 pathway inhibition
    Norihisa Uehara
    Department of Pathology II, Kansai Medical University, 10 15 Fumizono, Moriguchi, Osaka 570 8506, Japan
    Exp Eye Res 82:488-95. 2006
    ..This resulted in the retinal structure being protected. Therefore, NAM blocked MNU-induced photoreceptor cell apoptosis by inhibiting both PARP activity and the JNK/AP-1 signalling pathway...
  82. ncbi p53-dependent transcriptional regulation of the APC promoter in colon cancer cells treated with DNA alkylating agents
    A S Jaiswal
    Department of Anatomy and Cell Biology and the Shands Cancer Center, College of Medicine, The University of Florida, Gainesville, Florida 32610, USA
    J Biol Chem 276:18193-9. 2001
    ..However, the treatment of cells with DNA alkylating agents methylmethane sulfonate and N-methyl-N'-nitro-N-nitrosoguanidine, which cause phosphorylation of p53 at Ser(..
  83. ncbi Evidence in Escherichia coli that N3-methyladenine lesions induced by a minor groove binding methyl sulfonate ester can be processed by both base and nucleotide excision repair
    D Shah
    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198 6805, USA
    Biochemistry 40:1796-803. 2001
  84. ncbi Phorbol ester abrogates up-regulation of DNA polymerase beta by DNA-alkylating agents in Chinese hamster ovary cells
    D K Srivastava
    Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555 1068, USA
    J Biol Chem 270:16402-8. 1995
    ..polymerase, is known to be constitutively expressed in cultured cells, but treatment of cells with the DNA-alkylating agents MNNG or methyl methanesulfonate has been shown to up-regulate beta-pol mRNA level...
  85. ncbi Potential role of MLH1 in the induction of p53 and apoptosis by blocking transcription on damaged DNA templates
    Sunitha Yanamadala
    Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 0936, USA
    Mol Cancer Res 1:747-54. 2003
    ..we exposed the colon carcinoma cell line HCT116 (MLH1-deficient) and mlh1-corrected HCT116 sublines to alkylating agents or hydrogen peroxide (H2O2)...
  86. ncbi Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in hormone-insensitive metastatic breast cancer in complete remission compared with intensive standard-dose chemothera
    James J Vredenburgh
    Duke University Medical Center, Durham, North Carolina 27710, USA
    Biol Blood Marrow Transplant 12:195-203. 2006
    ..Salvage HDC converted 30% of partial responders to complete responders with similar survivals. The addition of novel targeted therapies to intensive-dose chemotherapy regimens may further improve survival in metastatic breast cancer...
  87. ncbi Base excision repair intermediates induce p53-independent cytotoxic and genotoxic responses
    Robert W Sobol
    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
    J Biol Chem 278:39951-9. 2003
  88. ncbi Histone H2AX is a critical factor for cellular protection against DNA alkylating agents
    J A Meador
    Department of Radiation Oncology, College of Physicians and Surgeons, Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
    Oncogene 27:5662-71. 2008
    ..Cellular sensitivity to two monofunctional alkylating agents (methyl methane sulfonate and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)) was dependent on H2AX dosage, and ..
  89. ncbi Cytogenetic and complementation analyses of recessive lethal mutations induced in the X chromosome of Drosophila by three alkylating agents
    J K Lim
    Genet Res 24:1-10. 1974
  90. pmc Contribution of base excision repair, nucleotide excision repair, and DNA recombination to alkylation resistance of the fission yeast Schizosaccharomyces pombe
    A Memisoglu
    Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    J Bacteriol 182:2104-12. 2000
    ..To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene...
  91. ncbi The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function
    A Blank
    Department of Pathology, University of Washington, Seattle, WA 98195 7705, USA
    DNA Repair (Amst) 3:629-38. 2004
  92. pmc Comparison of the genetic effects of equimolar doses of ENU and MNU: while the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia
    Liane B Russell
    Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 6420, USA
    Mutat Res 616:181-95. 2007
    ..g., chromosome aberrations, toxicity to germ cells and to animals, teratogenicity) revealed that while MNU is generally more effective, the opposite is true when the target cells are SG...
  93. ncbi Molecular dosimetry of alkylating agents: quantitative comparison of genetic effects on the basis of DNA adduct formation
    A A van Zeeland
    Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratories, State University of Leiden, The Netherlands
    Mutagenesis 3:179-91. 1988
  94. ncbi Kinetics of gamma-H2AX focus formation upon treatment of cells with UV light and alkylating agents
    Ori Staszewski
    Department of Toxicology, University of Mainz, Obere Zahlbacher Str 67, D 55131 Mainz, Germany
    Environ Mol Mutagen 49:734-40. 2008
    ..Here we show that DNA damage induced by alkylating agents [methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] and ultraviolet light (UV-C) ..
  95. ncbi MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents
    Bernd Kaina
    Department of Toxicology, University of Mainz, Obere Zahlbacher Str 67, D 55131 Mainz, Germany
    DNA Repair (Amst) 6:1079-99. 2007
    O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against alkylating agents that generate, among other lesions, O(6)-alkylguanine in DNA (collectively termed O(6)-alkylating agents [O(6)AA])...
  96. pmc Isolation and characterization of Escherichia coli K-12 mutants unable to induce the adaptive response to simple alkylating agents
    P Jeggo
    J Bacteriol 139:783-91. 1979
    When Esherichia coli cells are exposed to a low level of simple alkylating agents, they induce the adaptive response which renders them more resistant to the killing and the mutagenic effects of the same or other alkylating agents...
  97. pmc Distributed Drug Discovery, Part 2: global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D(3) catalog construction
    William L Scott
    Department of Chemistry and Chemical Biology, Indiana University Purdue University, Indianapolis, Indiana 46202 3274, USA
    J Comb Chem 11:14-33. 2009
    ..Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-..
  98. ncbi DNA mismatch repair deficiency stimulates N-ethyl-N-nitrosourea-induced mutagenesis and lymphomagenesis
    Nanna Claij
    Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
    Cancer Res 63:2062-6. 2003
    ..Mutation analysis of ENU-induced Hprt mutants revealed that base substitutions occurred predominantly at A-T base-pairs. These results suggest that MMR modulates the processing of ethylation damage at AT base-pairs...
  99. pmc Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice
    Dorothy Concepcion
    University of California San Diego School of Medicine, San Diego, California 92093 0644, USA
    Genetics 168:953-9. 2004
    ..This calibrates the nucleotide mutation rate for two mutagenesis centers, implies significance criteria for positional cloning efforts, and provides working estimates of effective genetic target sizes for selected phenotypes...
  100. ncbi Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis
    Bart M G Smits
    Hubrecht Laboratory, Utrecht, The Netherlands
    Pharmacogenet Genomics 16:159-69. 2006
    ..This study aims to provide the tools to manipulate the rat genome in a more directed way...
  101. ncbi Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice
    Timothy S Fenske
    Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Cancer Res 66:5029-38. 2006

Research Grants64

  1. HTS development for targeted anti-fungal small molecules
    Paul D Kaufman; Fiscal Year: 2010
    ..albicans lack H3K56 acetylation, and are highly sensitive to genotoxic agents including DNA alkylating agents and reactive oxygen species (ROS) such as hydrogen peroxide...
  2. Regulations of DNA Alkylation/Deamination Damage Repair
    Rabindra Roy; Fiscal Year: 2013
    Abstract Reactive nitrogen species, alkylating agents and lipid peroxide radicals generated endogenously and exogenously induce a myriad of DNA lesions, which is thought to affect genomic stability, cellular viability and cause multiple ..
  3. Role of Focal Adhesion Kinase (FAK) in Nephrosis and Nephritis
    Shuta Ishibe; Fiscal Year: 2013
    ..Angiotensin Converting Enzyme Inhibitor, Steroids, and Alkylating Agents. As many patients treated with these agents still progress to ESKD, this suggests that other mechanisms ..
  4. Regulatory Functions of APE1 acetylation
    KISHOR KUMAR BHAKAT; Fiscal Year: 2013 applicant): DNA base excision repair (BER) pathway repairs damage caused by reactive oxygen species, alkylating agents and ionizing radiation, and so protects cells against the toxic effects of various endogenous and exogenous ..
  5. The effects of dexamethasone on tumor and microglial cells in glioma
    TERREIA SUTTON JONES; Fiscal Year: 2013
    ..what effect Dex has on the effectiveness of the standard DNA damaging therapy for GBM such as radiation or alkylating agents. Our data from homogenized tumors and IHC studies from mice treated with Dex show that Dex suppresses the ..
  6. Systemic Chemotherapy of Melanoma: NMR Studies of Lonidamine &N-Mustard Activity
    Jerry D Glickson; Fiscal Year: 2013
    ..of melanoma by [tumor] selective [intracellular] acidification to sensitize melanomas to N-mustard alkylating agents. Our strategy is to coadminister glucose with the monocarboxylic acid transport (MCT) inhibitor lonidamine ..
  7. The Roles of Trm9 and tRNA Methylation in the DNA Damage Response
    Thomas J Begley; Fiscal Year: 2010
    Some environmental toxicants are alkylating agents that can damage DNA. If left un-repaired, DNA alkylation damage can lead to mutation, cell death, and can promote carcinogenesis...
  8. Novel small-molecule inhibitors of Wee1 kinase for medulloblastoma treatment
    Philip Reigan; Fiscal Year: 2013
    ..Current treatment for medulloblastoma includes surgical resection, radiation and chemotherapy with DNA alkylating agents, such as cisplatin...
  9. RNA Modifications as Biomarkers of Environmental Stress and Inflammation
    Thomas J Begley; Fiscal Year: 2013
    ..2[unreadable] modifications, and the expression of tRNA-related genes, before and after exposure of cells to alkylating agents and reactive oxygen and nitrogen species (RONS)...
  10. DNA cross-linking by diepoxybutane
    Natalia Y Tretyakova; Fiscal Year: 2013
    ..The long-range goal of our research is to establish the molecular mechanisms by which bifunctional alkylating agents elicit their biological effects...
  11. Development of Novel Inducers of Non-Apoptotic Cell Death to Target Glioblastoma
    William A Maltese; Fiscal Year: 2013
    ..Standard treatment involves surgery, followed by radiation and DNA alkylating agents like temozolomide...
  12. In vivo detection and genome-wide location analysis of DNA-adducts
    Stephen B Howell; Fiscal Year: 2013
    ..The long-term benefits of such research include the prediction of drug sensitivity or the study of epigenetic modifying compounds to rationalize combinations for optimal drug efficacy. ..
  13. Lentiviral-MGMT gene transfer into hematopoietic stem cells
    Stanton L Gerson; Fiscal Year: 2011
    ..The MGMT gene product (also known as AGT, O6-alkylguanine-DNA-alkyltransferase) repairs DNA damaged by alkylating agents. Hematopoietic progenitor cells (HP) can be transduced with a vector containing MGMT and selected for in ..
  14. Trial of mesna to prevent doxorubicin-induced plasma protein oxidation and TNFa r
    Jeffrey A Moscow; Fiscal Year: 2012 frequently given in combination chemotherapy regimens to prevent hemorrhagic cystitis associated with the alkylating agents ifosfamide and high-dose cyclophosphamide, and is commonly coincidentally co-administered with ..
  15. RCT of GnRH-a for ovarian protection during CYC therapy for rheumatic disease
    WILLIAM J MC CUNE; Fiscal Year: 2012
    ..This information will help guide women and their physicians making decisions regarding use of alkylating agents when preservation of ovarian function is desired...
  16. Novel approaches to enhance tumor cell cytotoxicity of alkylating agents
    Robert W Sobol; Fiscal Year: 2013
    ..However, as with many alkylating agents, drug resistance has limited its efficacy...
  17. Hematopoietic Stem Cell Development in Zebrafish
    YARIV J HOUVRAS; Fiscal Year: 2010
    ..studies characterizing HSCs, their unique sensitivity to DNA damaging agents such as ionizing radiation and alkylating agents has been appreciated...
  18. Mechanisms of selective excision and oxidative repair of alkylated DNA
    Manel Camps; Fiscal Year: 2013 their inhibition of DNA synthesis by polymerases, and this cytotoxicity is a rationale for the use of alkylating agents in cancer chemotherapy...
  19. A novel approach for quantitation of N-terminal valine adducts
    Gunnar Boysen; Fiscal Year: 2012
    ..proposed multi-adduct-monitoring method with alkylated peptide standards and globin treated in vitro with alkylating agents known to form N-terminal valine adducts;and (Aim 2) establish the suitability of the multi-adduct-monitoring ..
  20. Role of intrinsic apoptotic pathway in therapy-related myelodysplastic syndrome
    ELISE PETERSON LU; Fiscal Year: 2013
  21. Novel Glioma uPA Inhibitor Design Guided by Intracellular signaling Pathways
    Fredric A Gorin; Fiscal Year: 2010
    ..These hypoxic glioma populations have increased resistance to conventional radiation therapy coupled with alkylating agents such that cancer recurs in greater than 90% of individuals with high grade gliomas...
    Leona D Samson; Fiscal Year: 2013
    ..b>Alkylating agents are cytotoxic, mutagenic, clastogenic, teratogenic and carcinogenic, and they represent one of the most ..
  23. Etiology of Alkylator-Induced Myeloid Leukemia
    Michelle M Le Beau; Fiscal Year: 2012
    ..The most common type presents after a latency of ~5 years in patients who received alkylating agents, and is characterized by loss or deletion of chromosomes 5 and/or 7...
  24. DNA Polymerase Beta and Gastric Cancer
    DAWIT KIDANE MULAT; Fiscal Year: 2013
    ..It is well documented that dRP lyase activity of Pol ? protect cells from cytotoxicity of alkylating agents. Data showing that L22P lacks dRP lyase and has less DNA-binding affinity are consistent with the ..
  25. Amelioration of Vesicant-Induced Skin Injury by High Dose 25-Hydroxyvitamin D
    Kurt Lu; Fiscal Year: 2013
    ..Using human clinical samples obtained from ongoing trials of alkylating agents as well as murine skin samples obtained post-treatment with mechlorethamine we propose to assess: 1...
  26. Structure and Mechanisms of Styrene Monooxygenase
    George T Gassner; Fiscal Year: 2010
    ..and flavin-dependent monooxygenases, which catalyze epoxidation and hydroxylation reactions to yield strong alkylating agents and pulmonary irritants such as styrene oxide and vinyl phenols...
  27. Etiology of translocations in hematopoietic cells
    Christine A Richardson; Fiscal Year: 2012
    ..Chromosomal DSBs result following exposure to irradiation, alkylating agents, and topoisomerase II (topoII) inhibitors that are common therapies in the treatment of human cancers...
  28. The USC-JHU Cancer Epigenome Characterization Center
    Peter W Laird; Fiscal Year: 2013
    ..pilot was our finding of a link in glioblastoma multiforme between MGMT promoter methylation, treatment with alkylating agents, and a hypermutator phenotype associated with mismatch repair deficiency, an observation with potential ..
  29. Next-Generation Sequencing of Therapy-Related Acute Myeloid Leukemia
    ..syndrome (t-AML) is a complication that occurs in up to 10% of patients receiving chemotherapy with alkylating agents, topoisomerase II inhibitors, or radiation...
  30. Comparative Pharmaco-oncogenomics of Myeloma Drug Resistance
    Peter Leif Bergsagel; Fiscal Year: 2013
    The drug treatment of multiple myeloma is rapidly evolving, with four active classes of drugs (alkylating agents, glucocorticoids, proteasome inhibitors and Imids) being used in combinations with remarkable efficacy...
  31. Cross-links At Abasic Sites in Duplex DNA
    Yinsheng Wang; Fiscal Year: 2013
    ..cross-links in human cells exposed to agents that induce AP sites, including radiolysis and clinically-used alkylating agents and, (Aim 4) assess transcriptional bypass, replication, and repair of the dG-AP cross- link in human cells ..
    Sreenivas Kanugula; Fiscal Year: 2010
    ..Inactivation of hAGT by O6-benzylguanine (BG) has been shown to sensitize human tumors to these alkylating agents in cell culture and to improve the therapeutic index against human tumor xenografts in nude mice...
  33. Sapacitabine therapy to create synthetic lethality in DNA repair-deficient CLL
    WILLIAM GEORGE WIERDA; Fiscal Year: 2013
    ..fludarabine and other purine nucleoside analogs generated a significant improvement in responses relative to alkylating agents.1-3 Subsequently combinations of these two classes of agents, in particular fludarabine and cyclophosphamide,..
  34. Novel Organoboron Chemistry Utilizing Tetrahydroxydiborane
    Gary A Molander; Fiscal Year: 2013
    ..developed, a number of unique 2[unreadable] alkylating reagents, including amino alkylating and alkoxy alkylating agents, will be synthesized in enantiopure form, and protocols for their cross-coupling, based on secondary ..
  35. Bioinspired Enantioselective Catalytic alpha-Alkylation of Aldehydes
    SEAN M KEDROWSKI; Fiscal Year: 2013
    ..but it remains a challenge for synthetic chemists, despite considerable efforts using neutral, uncharged alkylating agents. The current proposal takes inspiration from nature and aims to develop a chiral small molecule amino-arene ..
  36. Role of the Shu Complex in Homology-directed Chromosome Repair
    WILLIAM GAINES; Fiscal Year: 2013
    ..HR) is an important tool for the repair of chromosomes injured by various mutagenic chemicals including alkylating agents and DNA cross-linking agents, and by ionizing radiations that cause DNA double strand breaks...
  37. Complications of Immunosupression for Eye Diseases
    John Kempen; Fiscal Year: 2009
    ..inhibitor therapy;2) a suggestions of increased risk of cancer mortality but not overall mortality with alkylating agents;and 3) no increased risk of overall and cancer mortality with antimetabolite, calcineurin inhibitor, and ..
    Joel M Linden; Fiscal Year: 2009
    ..Aim 3 will investigate the role and disulfide bond formation in AE and H2O2 action through analysis of thiol alkylating agents, epitope- tagged receptors, site-directed mutagenesis and protein sequencing...
  39. First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial
    Nisha Acharya; Fiscal Year: 2013
    ..These include the antimetabolites, calcineurin inhibitors, alkylating agents, and biologic drugs...
  40. Hypoxia-Activated O6-Benzylguanine Prodrugs
    ALAN CLAYTON SARTORELLI; Fiscal Year: 2012
    ..e., alkylating agents targeting the O6-position of DNA guanine)...
  41. Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation
    Michael P Stone; Fiscal Year: 2013
    ..Since DNA alkylating agents comprise a significant portion of the available chemotherapeutic drugs, knowledge of the spectrum of ..
    Renee Reijo Pera; Fiscal Year: 2000
    ..of the XRCC class of DNA repair genes protects cells against the lethal effects of ionizing radiation and alkylating agents. The XRCC1-complemented CHO cell line, EM9, is hypersensitive to many mutagenic agents, and demonstrates a ..
    Robert Ozols; Fiscal Year: 1992
    ..of glutathione S-transferase (GST) and increased ability of tumor cells to repair DNA damage produced by alkylating agents and cisplatin...
  44. Health Outcomes for Hodgkin Disease Survivors
    Debra Friedman; Fiscal Year: 2007
    ..Such therapeutic changes included a reduction the use of alkylating agents, authracyclines, and radiotherapy doses and fields, specifically to decrease adverse long-term outcomes in ..
  45. Biosynthesis of Pyrrolo[1,4]benzodiazepines, potent antitumor antibiotics
    Steven E Rokita; Fiscal Year: 2012
    ..a class of potent antitumor antibiotics found in actinomycetes, are sequence selective DNA alkylating agents. Phase 1 human clinical trials of SJG-136 for the treatment of metastatic or unresectable solid tumors were ..
  46. Role of human DNA polymerase iota in replicative bypass of DNA lesions
    Aneel K Aggarwal; Fiscal Year: 2013
    ..1-MeA and 3-dMeA are generated from exposure to environmental alkylating agents and from endogenous cellular reactions, and 1,3-butadiene is an important industrial chemical and an ..
    TOM E ELLENBERGER; Fiscal Year: 2011
    ..activities may ultimately be useful in treating cancers that have become resistant to DNA crosslinkers, alkylating agents, and other DNA-targeted therapies. PUBLIC HEALTH RELEVANCE: We are studying how damaged DNA is repaired...
    Owen Griffith; Fiscal Year: 2000
    DESCRIPTION: (Applicant's Abstract) Bifunctional alkylating agents (e.g., melphalan, cyclophosphamide, chlorambucil) and platinum antitumor compounds (e.g. cisplatin, carboplatin) are used to treat a wide range of human malignancies...
    Jun yan Hong; Fiscal Year: 2001
    A large number of environmental carcinogens and toxicants are alkylating agents. Human O6-alkylguanine-DNA alkyltransferase (AGT, EC 2.1.1...
    Shivendra Singh; Fiscal Year: 2003
    ..or valine) and 113 (alanine or valine), is believed to be an important mechanism in tumor cell to alkylating agents. Recent studies from our laboratory indicate that the I104,A113 isoform of hGSTP1-1 is significantly more ..
  51. Imaging of O6-Alkylguanine-DNA Alkyltransferase
    Ganesan Vaidyanathan; Fiscal Year: 2005 due to the repair of DNA lesions, generated by alkylation of guanine and thymine residues by the alkylating agents, by the repair protein O6 alkyl-DNA alkyltrasferase (AGT)...
    EDWARD SKIBO; Fiscal Year: 1992
    ..The proposed research involves the synthesis of the mitosene-like systems, DNA crosslinking studies, and antitumor screening. A DNA fragment of defined sequence will be employed to investigate the site of crosslinking...
    RICHARD BRANDA; Fiscal Year: 2000
    ..The first specific aim is to determine whether the combination of alkylating agents and nutritional folate deficiency causes an increased frequency of intragenic deletions in human stem cells ..
    Frederick Valeriote; Fiscal Year: 1990
    ..A number of alkylating agents will be examined including CCNU, L-PAM, cyclophosphamide and cis-platinium...
    Marvin Meistrich; Fiscal Year: 1992
    ..recovery of sperm production following a new clinical protocol for Stages I to III2B that does not employ alkylating agents; [2] understand the mechanisms by which hormonal manipulation protects spermatogenesis in experimental ..
    R Mulcahy; Fiscal Year: 1999
    ..are among the earliest and most common biochemical changes associated with inmate or acquired resistance to alkylating agents, analogs of cisplatinum and doxorubicin...
    Kenneth Tew; Fiscal Year: 1999
  58. Development of Anticancer 1,2-Bis(sulfonyl)hydrazines
    Alan Sartorelli; Fiscal Year: 2009
    DESCRIPTION (provided by applicant): Alkylating agents are among the most useful and extensively used anticancer agents;they occupy a central position in cancer chemotherapy...
  59. Global Responses to Aflatoxin B1 & Alkylating Agents
    Leona Samson; Fiscal Year: 2006
    ..model environmental agents to be studied are Aflatoxin B1 and its metabolites, plus a range of SNI and SN2 alkylating agents. Together these agents are representative of toxic agents found in the external environment, food supply, ..
    THOMAS BRENT; Fiscal Year: 1992
    There is compelling evidence that the response of human malignant tumors to chemotherapy with bifunctional alkylating agents is related to the extent of formation or rate of removal of DNA interstrand crosslinks...
    Leona D Samson; Fiscal Year: 2010
    ..tissues and animals (including people) protect against the cytotoxic, mutagenic and carcinogenic effects of alkylating agents present in our endogenous and exogenous environment...
  62. Conference Grant: "DNA Alkylation: From Natural Products to Chemotherapy"
    Kent Gates; Fiscal Year: 2006 a forum for discussion of current thinking regarding the chemical and biological mechanisms by which DNA-alkylating agents derive their medicinally useful properties...
    Michael Kennedy; Fiscal Year: 1992 of damaged cellular DNA is one mechanism which may allow tumor cells to develop resistance to alkylating agents. The coumeramycin antibiotic novobiocin can potentiate the cytotoxic effects of a number of alkylating ..
    Gordon Phillips; Fiscal Year: 1999
    The curability of selected cancers with certain chemotherapeutic drugs (notably alkylating agents) often has a direct relationship to dose in experimental systems, and admittedly with less data, in humans as well...