Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687051
Title: Combined chemo-radiotherapy utilising Olaparib and Mirin in combination with X-rays and targeted radionuclide therapy
Author: Galloway, Rhona Jane
ISNI:       0000 0004 5921 701X
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
Availability of Full Text:
Access through EThOS:
Access through Institution:
Abstract:
Introduction: Conventional radiotherapy efficacy is hampered by inefficient dose delivery to the target and normal tissue toxicity. Thus the use of more targeted radiotherapeutic tools such as targeted radionuclide therapy utilising for example 131I conjugated to metaiodobenzylguanidine (MIBG) is a more effective approach. Additionally, the development of new radiosensitising compounds is also at the forefront of cancer research. Mirin, an MRN complex inhibitor, and Olaparib, a PARP-1 inhibitor, are two such compounds that have been predicted to enhance radiotherapy Aims: The aims of the present study were to determine the radiosensitising potential of Mirin and Olaparib in combination with X-ray radiation and [131I]MIBG in vitro and interrogate the molecular mechanisms underpinning the cellular response to combination treatments. Results: Despite both X-ray radiation and [131I]MIBG eliciting a dose dependent reduction in cell survival, the pattern of activation of DNA repair proteins including ATM kinase, γ-H2AX and RAD51 varied greatly, demonstrating that the dynamics of DNA damage and repair, was much more prolonged with [131I]MIBG with respect to activation of DNA repair pathway components. There was also a variation in cells response to the two radiation qualities in combination with Mirin and Olaparib, with Mirin showing no radiosensitising effect with X-rays, however, significant radiosensitisation was observed in those exposed to Mirin and [131I]MIBG. Olaparib demonstrated effective radiosensitising potential when combined with both X-ray radiation and [131I]MIBG despite the difference in duration of DNA damaging effects. Conclusions: The radiosensitising potential of Mirin was dependant on radiation quality with a greater radiosensitisation seen with [131I]MIBG over X-irradiation. Conversely, Olaparib exerted tumour cell radiosensitisation regardless of radiation type. Additionally, mechanistic analyses indicated that Mirin is acting to efficiently inhibit the MRN-ATM directed DNA repair pathway in both cases therefore the lack of radiosensitisation produced with X-ray radiation is possibly as a result of residual or compensatory DNA repair.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.687051  DOI: Not available
Share: