Leicester Medical School
Department of Cancer Studies and Molecular Medicine

School of Medicine >> Cancer Studies and Molecular Medicine >> Staff >> Dr G Don Jones

Dr G Don Jones

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Rm 020

Senior Lecturer & Head of Group
Radiation and Oxidative Stress Group
Biocentre
University of Leicester
University Road
Leicester
LE1 7RH
UK

Don is Vice chair of the Association For Radiation Research. The Association's web site can be accessed here.

Research Interests:

Measurement, Mechanisms and Consequences of DNA Damage in Radiation Oncology, Chemotherapy and Chemical Carcinogenesis.

Radiotherapy and chemotherapy, used either singly or in combination, are two of the principal modalities of cancer treatment. For radiation and many chemotherapeutic drugs, genomic DNA is the primary cellular target for the damaging effects of these agents; indeed it is the DNA damage induced which is thought to be responsible for the killing of the cancer cells. To better understand, judge and improve treatment efficacy, it is the purpose of our research is to explore the mechanisms of these damaging interactions and to develop methods for the accurate measurement of DNA damage both in vitro and in vivo. Emphasis is placed on studying clinically relevant doses (avoiding the uncertainty of extrapolation from higher doses) and on translational research themes with anticipated patient benefit.

In addition to the above, we are also undertaking collaborative studies of chemical carcinogenesis; in particular an investigation of the biological significance of low levels of DNA adducts (in collaboration with Dr. Karen Brown, Cancer Biomarkers and Prevention Group (CBPG), development of analytical method for the detection of alkyl phosphotriesters (in collaboration with Dr. Don Jones & Prof. Peter Farmer CBPG) and elucidating the mechanisms of enhanced genotoxicity binary exposures (in collaboration with Dr. Keith McLuckie, CBPG & Dr. Michael Routledge, University of Leeds).

We possess expertise in many methods of radiogenic and adduct DNA damage measurement, in both total DNA and at specific gene loci, and in purposefully designed model target DNAs. The methods used include ³²P-postlabelling techniques for the measurement of radiogenic DNA damage and specific adduct formation, comet assay (single cell gel electrophoresis) for the measurement of DNA damage formation and repair in individual cells, and various PCR-based methods, to assess gene-specifc damage, including ligation mediated PCR to assess DNA gene damage at nucleotide resolution. Our studies also extend to the monitoring of early biological end-points (i.e. mutation) and correlation with genetic traits (i.e. genome and proteome expression status & polymorphisms).

Specific Research Projects include:

1. Comet assay studies of radiation- and drug-induced DNA damage: including, ‘Assessment of the alkaline comet assay as a rapid predictive test of radiotherapy in the treatment of bladder cancer’ and ‘Analysis of DNA damage and genetic features in 'in vitro' models treated with platinum based chemotherapeutic agents’
2. Studies to establish a genetic basis for bladder cancer cell radiation sensitivity
3. Development of new methods for the measurement of novel genotoxic markers including alkyl phosphotriesters
4. Consequences of single and combined genotoxic exposures: including, ‘Elucidating the mechanisms of enhanced genotoxicity of benzo[a]pyrene diol epoxide plus ultraviolet radiation binary exposures’
5. Correlation of DNA damage formation with mutation at nucleotide resolution in p53
6. Site-specific radical reactions in DNA
7. Investigation of the biological significance of low levels of DNA adducts derived from ethylene exposure

Funded Research:

‘Delineation and Exploitation of the Molecular Characteristics of Cancer Cell Radiosensitivity to Predict the Radiation Response of Tumours.’

The aim of this research is to evaluate the alkaline Comet assay and intrinsic markers of hypoxia (i.e. CA9 protein) as means of providing independent or co-dependent prognostic information in the radiation treatment of muscle-invasive bladder cancer. CRUK-funded.

‘Investigation of the Biological Significance of Low Levels of DNA Adducts Derived from Ethylene Exposure.’

The aim of the proposed study is a determination of the biological relevance of low levels of DNA adducts derived from ethylene exposure. To undertake this, we propose to investigate the dose response relationships for ethylene oxide (EO) derived DNA damage and biological effects (e.g. mutational events) and determine whether there is a level of tolerable DNA damage, below which significant increases in mutations are not induced, and also to determine what adduct profile (qualitative and quantitative) is associated with a biological response in terms of mutational change. Funded by CEFIC-LOSG of the European Chemical Industry Council. Principal Investigator Dr. Karen Brown, CBPG.

Our laboratory is also a member of a contributing partner (the ‘University of Leicester’ (ULEIC)) to a European Union-funded Network of Excellence (acronym ecnis). ecnis (‘Environmental Cancer Risk, Nutrition and Individual Susceptibility’) is a consortium of 21 laboratories to promote networking and inter-laboratory collaboration between ‘centres of excellence’ in the field of environmental cancer risk, nutrition and individual susceptibility.

Projects that have recently completed or close to completion include:

• ‘Does the Measurement of Specific Oxidative Damage at Sensitive Sites within Genes Correlate to Broad Biomarkers ?’, funded by MAFF/FSA;
• ‘Alkaline Comet Assay as a Rapid Predictive Test of Radiotherapy in the Treatment of Bladder Cancer’, funded by British Urological Foundation & Astrazeneca;
• ‘Analysis of DNA damage and genetic features in 'in vitro' models treated with platinum based chemotherapeutic agents’, funded by the Portuguese Government & EU.

List of Relevant Publications:

Comet assay studies of DNA damage

• AL Moneef, M., Sherwood, B.T., Bowman, K.J., Symonds, R.P., Kockelbergh, R.C., Mellon, J.K.,  Steward, W.P. and Jones, G.D.D., 2004, Comet assay measures of cis-platin and mitomycin C-induced DNA crosslink formation predicts bladder cancer cell chemosensitivity in vitro. Proceedings of the American Association for Cancer Research 45, 356 (abstract 1545).
• AL Moneef. M., Sherwood, B.T., Bowman, K.J., Kockelbergh, R.C., Symonds, R.P., Steward, W.P., Mellon, J.K. and Jones, G.D.D., 2003,  Measures by the alkaline comet assay predict bladder cancer cell radiosensitivity.  British Journal of Cancer, 89, 2271-2276.

New methods for the measurement of novel genotoxic markers

• Guichard, Y., Jones, G.D.D. and Farmer, P.F., 2000, Detection of DNA alkylphosphotriesters by 32P-postlabeling: the non-random manifestation of phosphotriester lesions in vivo.  Cancer Research, 60, 1276-1282.
• Bowman, K.J. Le Pla, R.C., Farmer, P.B., Guichard, Y. and Jones, G.D.D., 2001, Evaluation of phosphodiesterase I-based protocols for the detection of multiply damaged sites in DNA: the detection of tandem abasic, oxidative, and alkylative lesions in DNA oligonucleotides.  Nucleic Acids Res., 29, e101-e112.  
• Le Pla, R.C., Guichard, Y., Bowman, K.J., Farmer, P.B. and Jones, G.D.D., 2004, Further Development of 32P-Postlabelling for the Detection of Alkylphosphotriesters: Evidence for the long-term non-random manifestation of ethyl-phosphotriester adducts in vivo. Chemical Research in Toxicology, 17, 1491-1500.

Consequences of single and combined genotoxic exposures

• Limoli, C.L., Giedzinski, E., Morgan, W.F., Swarts, S.G., Jones, G.D.D. and Hyun, W., 2003, Persistent oxidative stress in chromosomally unstable cells.  Cancer Research, 63, 3107-3111.
• Routledge, M.N., McLuckie, K.I.E., Jones, G.D.D., Farmer, P.B. and Martin, E.A., 2001, The presence of benzo[a]pyrene diol epoxide adducts in target DNA leads to an increase in UV-induced DNA single strand breaks and supF gene mutations. Carcinogenesis, 22, 1231-1238.

Correlation of DNA damage formation with mutation

• Bowman, K.J., Guichard, Y., Langford, L., O'Connor, T.R., Routledge, M.R., Scott, G.B., Burns, P.A. and Jones, G.D.D., 2002, The relationship between in vitro oxidative damage formation and mutation at nucleotide resolution in p53. British Journal of Cancer 87, Supplement 1, S33  (Abstract 8.7).
• Bowman, K.J., Guichard, Y., Langford, L., O'Connor, T.R., Routledge, M.R., Scott, G.B., Burns, P.A. and Jones, G.D.D., 2002, Correlation of in vitro oxidative damage formation and mutation at nucleotide resolution in p53. Proceedings of the American Association for Cancer Research 43, 699 (Abstract 3463).

Site-specific radical reactions in DNA

• Doddridge, Z.A., Warner, J.L., Cullis, P.M. and Jones G.D.D., 1998,  UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides.  Chemical Communications, 18, 1997-1998.
• Doddridge, Z.A., Cullis, P.M., Jones G.D.D. and Malone, M.E., 1998,  7,8-Dihydro-8-oxo-2’-deoxyguanosine residues in DNA are radiation damage ‘hot’ spots in the direct gamma radiation damage pathway.  Journal of the American Chemical Society, 120, 10998-10999.