Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (42)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Margison, G. P.
Right arrow Articles by Povey, A. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Margison, G. P.
Right arrow Articles by Povey, A. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Mutagenesis, Vol. 17, No. 6, 483-487, November 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press

Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine

Geoffrey P. Margison1,4, Mauro F. Santibáñez Koref2 and Andrew C. Povey3

1 Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 4BX, UK, 2 Max Delbrück Centre for Molecular Medicine, Robert Rössle Strasse 10, Berlin 13 092, Germany and 3 Centre for Occupational and Environmental Health, University of Manchester, Manchester M13 9PL, UK

Alkylating agents are a structurally diverse group of compounds that cause a wide range of biological effects, including cell death, mutation and cancer. DNA damaged by these agents contains widely different amounts of 12 alkylated purines/pyrimidines and two phosphotriester isomers. The biological effects appear to be mediated predominantly by attack at the O6 position of guanine. DNA extracted from various normal human tissues contains detectable levels of O6-alkylguanine, the source of which has not been defined. Given that, following DNA replication, this lesion cannot only generate point mutations but can also initiate mismatch repair-mediated DNA recombination and cell death, it seems worthwhile to consider the possible contribution of these events and cell killing to the aetiology of human cancer. There is increasing evidence that point mutations are not the only mechanism involved in malignant transformation by alkylating agents. Some cancer chemotherapeutic agents exploit the cytotoxic effects of O6-alkylguanine and an understanding of the processing of this lesion has allowed strategies to be developed that should increase the effectiveness of such agents.

4 To whom correspondence should be addressed. Email: gmargison{at}picr.man.ac.uk


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CarcinogenesisHome page
H. A. Billson, K. L. Harrison, N. P. Lees, C. N. Hall, G. P. Margison, and A. C. Povey
Dietary variables associated with DNA N7-methylguanine levels and O6-alkylguanine DNA-alkyltransferase activity in human colorectal mucosa
Carcinogenesis, April 1, 2009; 30(4): 615 - 620.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Plummer, C. Jones, M. Middleton, R. Wilson, J. Evans, A. Olsen, N. Curtin, A. Boddy, P. McHugh, D. Newell, et al.
Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors
Clin. Cancer Res., December 1, 2008; 14(23): 7917 - 7923.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
L. E. Sandercock, J. N. Hahn, L. Li, H.A. Luchman, J. L. Giesbrecht, L. A. Peterson, and F. R. Jirik
Mgmt deficiency alters the in vivo mutational spectrum of tissues exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Carcinogenesis, April 1, 2008; 29(4): 866 - 874.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
L J Worrillow, A G Smith, K Scott, M Andersson, A J Ashcroft, G M Dores, B Glimelius, E Holowaty, G H Jackson, G L Jones, et al.
Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma
J. Med. Genet., March 1, 2008; 45(3): 142 - 146.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
P. Zhou, J. Teruya-Feldstein, P. Lu, M. Fleisher, A. Olshen, and R. L Comenzo
Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan
Blood, January 15, 2008; 111(2): 549 - 557.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. L. Eoff, K. C. Angel, M. Egli, and F. P. Guengerich
Molecular Basis of Selectivity of Nucleoside Triphosphate Incorporation Opposite O6-Benzylguanine by Sulfolobus solfataricus DNA Polymerase Dpo4: STEADY-STATE AND PRE-STEADY-STATE KINETICS AND X-RAY CRYSTALLOGRAPHY OF CORRECT AND INCORRECT PAIRING
J. Biol. Chem., May 4, 2007; 282(18): 13573 - 13584.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
N P Lees, K L Harrison, C N Hall, G P Margison, and A C Povey
Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents
Gut, March 1, 2007; 56(3): 380 - 384.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
S. K. Niture, C. S. Velu, Q. R. Smith, G.J. Bhat, and K. S. Srivenugopal
Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines
Carcinogenesis, February 1, 2007; 28(2): 378 - 389.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. S. Bobola, S. Varadarajan, N. W. Smith, R. D. Goff, D. D. Kolstoe, A. Blank, B. Gold, and J. R. Silber
Human Glioma Cell Sensitivity to the Sequence-Specific Alkylating Agent Methyl-Lexitropsin
Clin. Cancer Res., January 15, 2007; 13(2): 612 - 620.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. L. Eoff, A. Irimia, M. Egli, and F. P. Guengerich
Sulfolobus solfataricus DNA Polymerase Dpo4 Is Partially Inhibited by "Wobble" Pairing between O6-Methylguanine and Cytosine, but Accurate Bypass Is Preferred
J. Biol. Chem., January 12, 2007; 282(2): 1456 - 1467.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. S. Mijal, S. Kanugula, C. C. Vu, Q. Fang, A. E. Pegg, and L. A. Peterson
DNA Sequence Context Affects Repair of the Tobacco-Specific Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by Human O6-Alkylguanine-DNA Alkyltransferases.
Cancer Res., May 1, 2006; 66(9): 4968 - 4974.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
P. D. Terry and M. Goodman
Is the Association between Cigarette Smoking and Breast Cancer Modified by Genotype? A Review of Epidemiologic Studies and Meta-analysis.
Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 602 - 611.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. J. Pearson, S. Wharton, A. J. Watson, G. Begum, A. Butt, N. Glynn, D. M. Williams, T. Shibata, M. F. Santibanez-Koref, and G. P. Margison
A novel DNA damage recognition protein in Schizosaccharomyces pombe.
Nucleic Acids Res., January 1, 2006; 34(8): 2347 - 2354.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
G. P. Margison, J. Heighway, S. Pearson, G. McGown, M. R. Thorncroft, A. J. Watson, K. L. Harrison, S. J. Lewis, K. Rohde, P. V. Barber, et al.
Quantitative trait locus analysis reveals two intragenic sites that influence O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells
Carcinogenesis, August 1, 2005; 26(8): 1473 - 1480.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. J. Pearson, J. Ferguson, M. Santibanez-Koref, and G. P. Margison
Inhibition of O6-methylguanine-DNA methyltransferase by an alkyltransferase-like protein from Escherichia coli
Nucleic Acids Res., July 13, 2005; 33(12): 3837 - 3844.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
E. R. Plummer, M. R. Middleton, C. Jones, A. Olsen, I. Hickson, P. McHugh, G. P. Margison, G. McGown, M. Thorncroft, A. J. Watson, et al.
Temozolomide Pharmacodynamics in Patients with Metastatic Melanoma: DNA Damage and Activity of Repair Enzymes O6-Alkylguanine Alkyltransferase and Poly(ADP-Ribose) Polymerase-1
Clin. Cancer Res., May 1, 2005; 11(9): 3402 - 3409.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. S. Bobola, J. R. Silber, R. G. Ellenbogen, J. R. Geyer, A. Blank, and R. D. Goff
O6-Methylguanine-DNA Methyltransferase, O6-Benzylguanine, and Resistance to Clinical Alkylators in Pediatric Primary Brain Tumor Cell Lines
Clin. Cancer Res., April 1, 2005; 11(7): 2747 - 2755.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
E. T. Donnelly, H. Bardwell, G. A. Thomas, E. D. Williams, M. Hoper, P. Crowe, W. G. McCluggage, M. Stevenson, D. H. Phillips, A. Hewer, et al.
Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical
Carcinogenesis, May 1, 2004; 25(5): 847 - 855.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
C. R. Calabrese, R. Almassy, S. Barton, M. A. Batey, A. H. Calvert, S. Canan-Koch, B. W. Durkacz, Z. Hostomsky, R. A. Kumpf, S. Kyle, et al.
Anticancer Chemosensitization and Radiosensitization by the Novel Poly(ADP-ribose) Polymerase-1 Inhibitor AG14361
J Natl Cancer Inst, January 7, 2004; 96(1): 56 - 67.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Z. Fang, Y. Wang, N. Ai, Z. Hou, Y. Sun, H. Lu, W. Welsh, and C. S. Yang
Tea Polyphenol (-)-Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase and Reactivates Methylation-Silenced Genes in Cancer Cell Lines
Cancer Res., November 15, 2003; 63(22): 7563 - 7570.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
S. Yanamadala and M. Ljungman
Potential Role of MLH1 in the Induction of p53 and Apoptosis by Blocking Transcription on Damaged DNA Templates
Mol. Cancer Res., August 1, 2003; 1(10): 747 - 754.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.