A number of epidemiological studies have associated anticancer therapy with an increased risk of cardiovascular disease in later life, a concern for patient long-term survival. Survivors of childhood cancer, previously administered radiotherapy, display chronic arterial damage including endothelial cell dysfunction, a defining feature of atherosclerosis (Brouwer et al., 2013). This thesis aimed to characterise the effects of radiation therapy (X-rays) and the cardiotoxic chemotherapeutic drug doxorubicin, alone or in combination, on coronary artery endothelial cell viability and function. The role of stress-activated c-Jun N-terminal kinase (JNK) in therapy-mediated endothelial cell dysfunction was also elucidated. Survival assays, employed to assess the effects of single-agent therapy, demonstrated that doxorubicin causes concentration-dependent death of human coronary artery endothelial cells (HCAECs) and X-irradiation inhibits HCAEC clonogenic survival dose-dependently. Using fluorescence-activated cell sorting (FACS), the ability of doxorubicin to arrest HCAECs in the radiosensitive G2/M phase of the cell cycle after a period of 24 hours was identified. Nonetheless, when doxorubicin and X-rays were used in combination, synergy between the two agents was not observed, an additive effect on HCAEC clonogenic survival was detected at the specific concentration (1 μM doxorubicin) and dose (1 Gy X-rays) studied. JNK was moderately activated by doxorubicin and played a partial role in the G2/M arrest of HCAECs by doxorubicin. Surprisingly, X-irradiation poorly activated JNK, thus JNK does not appear to play a major role in endothelial cell dysfunction post-therapy with these anticancer agents. The data collated in this thesis provides an insight into the endothelial cell dysfunction and death elicited by anticancer agents, doxorubicin and X-rays, contributing to vascular wall destruction and development of atherosclerosis post-cancer therapy.
|Date of Award||16 Feb 2018|
- University Of Strathclyde
|Sponsors||British Heart Foundation BHF & University of Strathclyde|
|Supervisor||Robin Plevin (Supervisor) & Marie Boyd (Supervisor)|