The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy

dc.contributor.advisorBlekkenhorst, Gerhardus Hendrikusen_ZA
dc.contributor.authorKent, Charlesen_ZA
dc.date.accessioned2017-12-11T14:15:56Z
dc.date.available2017-12-11T14:15:56Z
dc.date.issued1990en_ZA
dc.description.abstractIt has long been known that oxygen has the potential to be toxic to biologic systems and that this toxicity is not due to oxygen itself, but due to the production of oxygen radicals. One of these potentially toxic radicals, superoxide (O₂⁻) can be generated as a result of ionizing radiation, and if not adequately removed can proceed to cause cell damage. Superoxide dismutase (SOD) is one of the key enzymes involved in the defence against oxygen toxicity. SOD activity can be inhibited by diethyldithiocarbamate (DOC), a powerful copper chelator. If inhibition of SOD by DOC increases the lifetime and effectiveness of radiation induced O₂⁻, it follows that the potential exists for DOC to enhance the effect of radiation. DOC is however also a thiol compound, and thus may act as a radioprotector by modifying tissue oxygenation status or by free radical scavenging. This study has concerned itself primarily with the inhibition of superoxide dismutase by diethyldithiocarbamate in order to sensitize tumours to ionizing radiation. The use of DOC as an inhibitor of SOD has however meant that any sensitization resulting from SOD inhibition could be masked by a radioprotective effect by DOC. The inhibition of SOD by DDC was confirmed in a murine rhabdomyosarcoma, and it was shown that this inhibition can be maintained for up to twenty-four hours after DDC administration. It was hypothesised that there was a potential for the radioprotective effect of DDC to be overcome, if the levels of DDC were low enough at the time of irradiation. Indeed, if DDC was removed from the growth medium of B16 mouse melanoma cells in culture prior to irradiation, a significant sensitization was demonstrated. It was shown that DDC could act as both a radiosensitizer and as a radioprotector in the same experiment. The dominant action of DDC was found to be dependent on the time allowed between DDC administration and irradiation. If this time was approximately 4 hours, it was possible to show a radiosensitizing effect by means of a tumour growth delay assay. This time modulation effect of DOC was shown in larger tumours, rather than smaller tumours, which could indicate that tumour oxygenation is an important criterion in determining the response to radiation of DOC treated cells. It was shown that B16 mouse melanoma cells exposed to 43°C after DDC pre-treatment were sensitized to thermal damage. This work suggests that some caution should be exercised when DDC is put forward as either a radiosensitizer or a radioprotector in the clinic, but that DDC may have potential as a thermosensitizer.en_ZA
dc.identifier.apacitationKent, C. (1990). <i>The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Radiology. Retrieved from http://hdl.handle.net/11427/26550en_ZA
dc.identifier.chicagocitationKent, Charles. <i>"The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Radiology, 1990. http://hdl.handle.net/11427/26550en_ZA
dc.identifier.citationKent, C. 1990. The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Kent, Charles AB - It has long been known that oxygen has the potential to be toxic to biologic systems and that this toxicity is not due to oxygen itself, but due to the production of oxygen radicals. One of these potentially toxic radicals, superoxide (O₂⁻) can be generated as a result of ionizing radiation, and if not adequately removed can proceed to cause cell damage. Superoxide dismutase (SOD) is one of the key enzymes involved in the defence against oxygen toxicity. SOD activity can be inhibited by diethyldithiocarbamate (DOC), a powerful copper chelator. If inhibition of SOD by DOC increases the lifetime and effectiveness of radiation induced O₂⁻, it follows that the potential exists for DOC to enhance the effect of radiation. DOC is however also a thiol compound, and thus may act as a radioprotector by modifying tissue oxygenation status or by free radical scavenging. This study has concerned itself primarily with the inhibition of superoxide dismutase by diethyldithiocarbamate in order to sensitize tumours to ionizing radiation. The use of DOC as an inhibitor of SOD has however meant that any sensitization resulting from SOD inhibition could be masked by a radioprotective effect by DOC. The inhibition of SOD by DDC was confirmed in a murine rhabdomyosarcoma, and it was shown that this inhibition can be maintained for up to twenty-four hours after DDC administration. It was hypothesised that there was a potential for the radioprotective effect of DDC to be overcome, if the levels of DDC were low enough at the time of irradiation. Indeed, if DDC was removed from the growth medium of B16 mouse melanoma cells in culture prior to irradiation, a significant sensitization was demonstrated. It was shown that DDC could act as both a radiosensitizer and as a radioprotector in the same experiment. The dominant action of DDC was found to be dependent on the time allowed between DDC administration and irradiation. If this time was approximately 4 hours, it was possible to show a radiosensitizing effect by means of a tumour growth delay assay. This time modulation effect of DOC was shown in larger tumours, rather than smaller tumours, which could indicate that tumour oxygenation is an important criterion in determining the response to radiation of DOC treated cells. It was shown that B16 mouse melanoma cells exposed to 43°C after DDC pre-treatment were sensitized to thermal damage. This work suggests that some caution should be exercised when DDC is put forward as either a radiosensitizer or a radioprotector in the clinic, but that DDC may have potential as a thermosensitizer. DA - 1990 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1990 T1 - The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy TI - The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy UR - http://hdl.handle.net/11427/26550 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/26550
dc.identifier.vancouvercitationKent C. The potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapy. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Radiology, 1990 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/26550en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Radiologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherDitiocarben_ZA
dc.subject.otherRadiobiologyen_ZA
dc.subject.otherRadiotherapyen_ZA
dc.subject.otherSuperoxide Dismutase - antagonists & inhibitorsen_ZA
dc.titleThe potential of the superoxide dismutase inhibitor, diethyldithiocarbamate as an adjuvant to radiotherapyen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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