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

• Main Author: Cran, Jordan Darice
• Language: English
• Published: University of British Columbia 2013
• Online Access: http://hdl.handle.net/2429/44337

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.