Selenium as a Modulator of Efficacy and Toxicity of Chemotherapy and Radiation
Lobb, R. (2011). Selenium as a Modulator of Efficacy and Toxicity of Chemotherapy and Radiation (Thesis, Master of Science (MSc)). University of Waikato, Hamilton, New Zealand. Retrieved from https://hdl.handle.net/10289/5709
Permanent Research Commons link: https://hdl.handle.net/10289/5709
Selenium (Se) is an essential trace mineral required in maintaining health in humans. Recent research has demonstrated that Se shows promise as an agent that can reduce the harmful side-effects of chemotherapy (CT) and radiotherapy (RT), while not compromising the effectiveness of treatment. Clinical evaluations using varying doses of Se have demonstrated a significant reduction in toxicity of CT and RT. Se supplementation appears to mediate its biological effects through four main mechanisms: Se treatment promotes the death of malignant cells, but not normal cells, through the differential effects on the endoplasmic reticulum stress response; it inhibits hypoxia-induced angiogenesis which is required by tumours for their blood supply; it enhances DNA repair in normal but not malignant cells; and it reverses cellular resistance to some cytotoxic drugs. The objectives of this thesis were to evaluate the biological characteristics of the differential impact of a Se compound, methylseleninic acid (MSA), on malignant and non-malignant human cells and how that modulates the effects of cisplatin chemotherapy and/or radiation. In parallel with this, similar evaluations were undertaken in patients receiving a Se compound or placebo in conjunction with cisplatin and radiation for head and neck squamous cell carcinoma (HNSCC). MSA induced differential effects in peripheral blood mononuclear cells (PBMC) obtained from healthy individuals compared to the monocytic leukaemia THP-1 cell-line. While MSA did not change PBMC viability, it reduced that of THP-1 cells in a concentration-dependent manner. Furthermore, MSA treatment enhanced the cytotoxicity of CT and RT toward THP-1 cells without compromising the survival of PBMC. This increased sensitivity in THP-1 cells is likely to be related to significantly reduced levels of intracellular glutathione (GSH) in response to MSA. In contrast, GSH levels in PBMC rose substantially in response to MSA. Assessment of ER stress response proteins revealed that pro-survival proteins (GRP78, phospho-eIF2α, and spliced XBP-1) were upregulated in PBMC in response to MSA treatment. The malignant THP-1 cells had high levels of pro-survival proteins at baseline, which increased to a variable degree, especially caspase-8, in response to MSA. Putative pharmacodynamic markers of biological activity of Se were evaluated in plasma samples and PBMC from HNSCC patients in a randomised, placebo-controlled, double-blind phase II trial. Patients were treated with a 7-week radical course of concurrent cisplatin and RT (CRT) and were randomised to receive either selenomethionine (SLM) or matching placebo for 11 weeks, starting a week prior to CRT treatment. Because the trial is not yet complete, treatment allocation remains blinded and thus the pharmacodynamic results according to treatment with SLM or placebo cannot be made at the time of writing this thesis. However, markers of angiogenesis and the selenoprotein glutathione peroxidise 3 were measured and shown to significantly change during the course of treatment in a patient-specific manner. Lastly, ER stress markers were shown to be detected in PBMC obtained from patients during treatment. Se compounds differentially affect non-malignant and malignant cells. This results in increased therapeutic efficacy of cisplatin and RT targeting malignant cells. These effects appear to be mediated, at least in part, by modulation of intracellular GSH and ER stress response proteins
University of Waikato
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