Development of clinical biomarkers of DNA double strand breaks for cancer care
<p>Many anticancer therapies, including radiotherapy, act by damaging the deoxyribosenucleic acid (DNA) that is fundamental to cell function and proliferation. H2AX is a histone protein associated with DNA that is phosphorylated to produce γH2AX in response to DNA double strand breaks (DSBs),...
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| Format: | Thesis |
| Language: | English |
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2012
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| _version_ | 1817932576951631872 |
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| author | Shah, K |
| author2 | Vallis, K |
| author_facet | Vallis, K Shah, K |
| author_sort | Shah, K |
| collection | OXFORD |
| description | <p>Many anticancer therapies, including radiotherapy, act by damaging the deoxyribosenucleic acid (DNA) that is fundamental to cell function and proliferation. H2AX is a histone protein associated with DNA that is phosphorylated to produce γH2AX in response to DNA double strand breaks (DSBs), the most lethal lesions caused in cancer cells. This thesis examines the translation of γH2AX detection assays to clinical situations in order to provide biomarkers of response that might help to guide the treatment of cancer patients.</p> <p>γH2AX immunohistochemistry was developed in preclinical xenograft models, and validated over a range of radiation doses and over time after irradiation. The method was prepared for translation to archived clinical biopsy and surgical specimens.</p> <p>The DSB Biomarkers Pilot Study was established in order to develop a method for γH2AX quantification in direct tumour cell specimens obtained using the clinical technique of fine needle aspiration (FNA) cytology. Eleven patients undergoing anticancer therapy were recruited to the study, and the method evaluated. The coefficient of variation of the measure was 49%.</p> <p>Non-invasive imaging for γH2AX would allow DNA damage to be quantified in all tumour sites, and on multiple occasions. An antibody-based nuclear medicine imaging agent was re-engineered using Fab fragments of the antibody. The novel agent demonstrated improved pharmacokinetics when compared to the whole antibody agent, but reduced target specificity.</p> <p>The findings further develop the potential to exploit DNA damage biomarker measurements in clinical oncology.</p> |
| first_indexed | 2024-03-07T08:18:18Z |
| format | Thesis |
| id | oxford-uuid:2e6b2595-fbbc-4fff-80e2-bec8a4d9d15e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:40:07Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:2e6b2595-fbbc-4fff-80e2-bec8a4d9d15e2024-12-07T11:02:17ZDevelopment of clinical biomarkers of DNA double strand breaks for cancer careThesishttp://purl.org/coar/resource_type/c_db06uuid:2e6b2595-fbbc-4fff-80e2-bec8a4d9d15eRadiation chemistryTumoursOncologyRadiationMedical SciencesDNA damage signallingEnglishOxford University Research Archive - Valet2012Shah, KVallis, K<p>Many anticancer therapies, including radiotherapy, act by damaging the deoxyribosenucleic acid (DNA) that is fundamental to cell function and proliferation. H2AX is a histone protein associated with DNA that is phosphorylated to produce γH2AX in response to DNA double strand breaks (DSBs), the most lethal lesions caused in cancer cells. This thesis examines the translation of γH2AX detection assays to clinical situations in order to provide biomarkers of response that might help to guide the treatment of cancer patients.</p> <p>γH2AX immunohistochemistry was developed in preclinical xenograft models, and validated over a range of radiation doses and over time after irradiation. The method was prepared for translation to archived clinical biopsy and surgical specimens.</p> <p>The DSB Biomarkers Pilot Study was established in order to develop a method for γH2AX quantification in direct tumour cell specimens obtained using the clinical technique of fine needle aspiration (FNA) cytology. Eleven patients undergoing anticancer therapy were recruited to the study, and the method evaluated. The coefficient of variation of the measure was 49%.</p> <p>Non-invasive imaging for γH2AX would allow DNA damage to be quantified in all tumour sites, and on multiple occasions. An antibody-based nuclear medicine imaging agent was re-engineered using Fab fragments of the antibody. The novel agent demonstrated improved pharmacokinetics when compared to the whole antibody agent, but reduced target specificity.</p> <p>The findings further develop the potential to exploit DNA damage biomarker measurements in clinical oncology.</p> |
| spellingShingle | Radiation chemistry Tumours Oncology Radiation Medical Sciences DNA damage signalling Shah, K Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title | Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title_full | Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title_fullStr | Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title_full_unstemmed | Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title_short | Development of clinical biomarkers of DNA double strand breaks for cancer care |
| title_sort | development of clinical biomarkers of dna double strand breaks for cancer care |
| topic | Radiation chemistry Tumours Oncology Radiation Medical Sciences DNA damage signalling |
| work_keys_str_mv | AT shahk developmentofclinicalbiomarkersofdnadoublestrandbreaksforcancercare |