Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase

The presence of tumour hypoxia, regions of low levels of oxygen, is a distinct and exploitable feature of the solid tumour microenvironment. While its presence is generally accepted as a negative prognostic indicator, hypoxia is a relatively unique feature to solid tumours and can therefore be explo...

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Main Author: Cran, Jordan Darice
Language:English
Published: University of British Columbia 2013
Online Access:http://hdl.handle.net/2429/44337
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spelling ndltd-LACETR-oai-collectionscanada.gc.ca-BVAU.2429-443372014-03-26T03:39:31Z Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase Cran, Jordan Darice The presence of tumour hypoxia, regions of low levels of oxygen, is a distinct and exploitable feature of the solid tumour microenvironment. While its presence is generally accepted as a negative prognostic indicator, hypoxia is a relatively unique feature to solid tumours and can therefore be exploited as a means to specifically target cancer cells in this setting. Prodrugs can be designed to harness the reductive environment found within hypoxic cells, by releasing an active drug following reduction. This work continues the development of a prodrug, Hapi3, which under hypoxic conditions releases an inhibitor of the DNA-dependent protein kinase (DNA-PK). DNA-PK is the central component to the non-homologous end joining pathway (NHEJ) used to repair double strand breaks and base damage induced by ionizing radiation (IR). Inhibition of repair within hypoxic environments in conjunction with IR provides a means to selectively target tumour cells. Previously, clonogenic survival was used to determine that Hapi3 provides a sensitization enhancement ratio of 1.8 and does not release the active inhibitor, IC86621, under normoxic conditions. The objective of this research is to evaluate formulations of Hapi3 in mice to achieve desirable tissue concentrations for radiosensitization and perform efficacy studies to determine if hypoxic inhibition of repair will improve the efficacy radiation therapy in an in vivo tumour model. Due to Hapi3 solubility limitations, the dose necessary to achieve radiosensitization in tissues was not achieved as evidenced by a lack of observable growth delay. Compounds based on IC86621 are unsuitable for further development, however syntheses of new hypoxia activated repair inhibitors should be pursued. 2013-04-19T18:52:24Z 2013-04-20T09:13:48Z 2013 2013-04-19 2013-05 Electronic Thesis or Dissertation http://hdl.handle.net/2429/44337 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ Attribution-NonCommercial 2.5 Canada University of British Columbia
collection NDLTD
language English
sources NDLTD
description The presence of tumour hypoxia, regions of low levels of oxygen, is a distinct and exploitable feature of the solid tumour microenvironment. While its presence is generally accepted as a negative prognostic indicator, hypoxia is a relatively unique feature to solid tumours and can therefore be exploited as a means to specifically target cancer cells in this setting. Prodrugs can be designed to harness the reductive environment found within hypoxic cells, by releasing an active drug following reduction. This work continues the development of a prodrug, Hapi3, which under hypoxic conditions releases an inhibitor of the DNA-dependent protein kinase (DNA-PK). DNA-PK is the central component to the non-homologous end joining pathway (NHEJ) used to repair double strand breaks and base damage induced by ionizing radiation (IR). Inhibition of repair within hypoxic environments in conjunction with IR provides a means to selectively target tumour cells. Previously, clonogenic survival was used to determine that Hapi3 provides a sensitization enhancement ratio of 1.8 and does not release the active inhibitor, IC86621, under normoxic conditions. The objective of this research is to evaluate formulations of Hapi3 in mice to achieve desirable tissue concentrations for radiosensitization and perform efficacy studies to determine if hypoxic inhibition of repair will improve the efficacy radiation therapy in an in vivo tumour model. Due to Hapi3 solubility limitations, the dose necessary to achieve radiosensitization in tissues was not achieved as evidenced by a lack of observable growth delay. Compounds based on IC86621 are unsuitable for further development, however syntheses of new hypoxia activated repair inhibitors should be pursued.
author Cran, Jordan Darice
spellingShingle Cran, Jordan Darice
Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
author_facet Cran, Jordan Darice
author_sort Cran, Jordan Darice
title Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
title_short Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
title_full Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
title_fullStr Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
title_full_unstemmed Development of a hypoxia activated prodrug for the selective inhibition of DNA-dependent protein kinase
title_sort development of a hypoxia activated prodrug for the selective inhibition of dna-dependent protein kinase
publisher University of British Columbia
publishDate 2013
url http://hdl.handle.net/2429/44337
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