Doctoral Degrees ( Radiobiology)

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Novel treatment strategies for breast, lung and cervical cancer
(Stellenbosch : Stellenbosch University, 2019-12) Hamid, Mogammad Baahith; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiobiology.
ENGLISH SUMMARY : Cancer continues to be a global health burden, especially in the economically developing regions. The complex nature of this cancer contributes to a range of clinical challenges. Breast, lung and cervical cancer are known to have the highest incidence and mortality rates globally. Although many therapeutic options are available to treat cancer, the efficacy of most therapies is hindered due to normal tissue toxicity and tumour resistance. Novel treatment strategies are thus warranted to address clinical challenges and significantly improve patient outcomes. More than 50% of cancer patients receive radiotherapy throughout their illness. DNA damage resulting in cell death, as a consequence of ionising radiation exposure, has assisted in clinical tumour management. However, inherent and acquired resistance as well as the manipulation of essential pathways, like cell metabolism, have aided cancer cells to evade the toxic effects of radiotherapy. Increasing the therapeutic window of this treatment modality may benefit a large number of patients. There is evidence to suggest that ionising radiation may activate cell survival signalling pathways. Targeting the components of these pathways may modify cell metabolism and significantly radiosensitise cancer cells. Therefore, combining targeted therapy and ionising radiation may be a viable therapeutic strategy. The objective of this study was to inhibit molecular targets of key pathways which regulate cell survival, and expose breast, lung, cervical cancer and normal cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability and effect on cellular metabolic activity. In this study, clonogenic assays were performed to determine the relative sensitivity of 6 cell lines (cancer: MDA-MB-231 (breast), MCF-7 (breast), HeLa (cervix) and A549 (lung); apparently normal: L132 (lung) and MCF-12A (breast)) to ionising radiation and inhibitor therapy. Mathematic modelling was used to determine the mode of interaction between EGFR, PI3K/mTOR, and BcL-2 inhibitors, as well as, the modifying effects of inhibitors on the radiosensitivity and metabolic activity of the cell lines. This study found that potential therapeutic benefit might be obtained by treating MDA-MB-231, MCF-7, HeLa and A549 cells with X-rays. The MCF-7 cell line showed the highest potential of therapeutic benefit with a greater than 2-fold higher radiosensitivity, relative to the normal MCF-12A cells. The A549 cell line showed the lowest potential for therapeutic benefit, when compared with the L132 cell line. Inhibition of PI3K and mTOR with NVP-BEZ235 resulted in a significant therapeutic benefit for the lung and cervical cancer cell lines, minor therapeutic benefit in the MCF-7 cell line, and no benefit for the MDA-MB-231 cell line. Bcl-2 inhibition with ABT-263 had either no effect on the MDA-MB-231 and A549 cell lines or resulted in potential therapeutic benefits for MCF-7 and HeLa cell lines. Pre-treatment of breast (MDA-MB-231 and MCF-7) and lung (A549) cancer cell lines with a cocktail of an EGFR (AG-1478), PI3K/mTOR (NVP-BEZ235), or Bcl-2 (ABT-263) inhibitors had an enhancing effect on radiosensitivity and cellular metabolic activity. The same treatment provided radioprotection, and reduced the metabolic activity of the cervical cancer cell line, HeLa. These findings suggest that concurrent inhibition of EGFR, PI3K, mTOR, and Bcl-2 during radiotherapy might improve the treatment response of breast and lung cancer in patients. Future studies validating these findings for lower inhibitor concentrations might be more relevant in the clinical setting, as systemic toxicity is a major concern. A study exposing cells to fractionated radiotherapy, after inhibitor pre-treatment, may further reveal the therapeutic potential of the inhibitors used in this study. Evaluating the effect of inhibitor pre-treatment and radiofrequency field, which have been shown to exhibit radiomodulatory effects on cancer and normal cell lines, may provide insight into the development of a novel therapeutic strategy.
Evaluation of the effect of radiofrequency electromagnetic waves on radiosensitivity
(Stellenbosch : Stellenbosch University, 2019-12) Chinhengo, Angela; Akudugu, J. M.; Serafin, A. M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiobiology.
ENGLISH SUMMARY : Cancer is a major cause of human death worldwide, and one of the very real challenges is how to control treatment resistance. An additional challenge is the co-morbidity of cancer, with certain infections complicating its management. Radiotherapy (RT) is considered the first line of treatment for most superficial cancers, as these malignancies tend to respond well to radiation. The use of hypofractionated treatment may be beneficial for certain tumours, but hypofractionation may result in severe side-effects from normal tissue toxicity from which the patient may not recover. To circumvent this, radiation modifying agents that potentiate the tumour inactivating effects of ionising radiation and thereby lead to a reduction in radiation dose and prevent normal tissue toxicity, can be utilised. Magnetic fields have long been suggested as potential enhancers of radiation effects. Studies on the combined biological effects of radiofrequency fields (RFF) and ionising radiation are virtually non-existent. The use of RFF adjuvant to radiotherapy may be beneficial, as they have been shown to exhibit in vitro radiosensitising and radioprotective effects in malignant and normal cells, respectively, with the possibility of a significant dose reduction. There is, however, a need to understand the mechanisms by which these RFF influence radiosensitivity so that they can be employed efficiently as radiotherapy modulators. The main goal of radiotherapy is to kill tumour cells and spare normal tissue, and a good modifying agent would be one that sensitises the tumour whilst protecting normal tissue. This study assessed the effect of radiofrequency fields (RFF), modulated at 100, 1000, 2000 and 4000 Hz, on the radiosensitivity of four cell lines: a p53 mutant melanoma cell line, MeWo; a p53 wild-type melanoma cell line, Be11; a p53 mutant prostate cancer cell line, DU145; and a p53 wild-type normal lung fibroblast cell line, L132. The radiomodulatory effect of radiofrequency fields was evaluated using the colony assay. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), superoxide dismutase (SOD) and micronucleus assays were used to assess the possible mechanisms by which radiofrequency fields influence the radiosensitivity of cells. The data demonstrate that radiofrequency fields are more efficient in modulating large fractional doses of X-rays and could find application in hypofractionated radiotherapy as adjuvants, especially for tumours with low alpha/beta ratios. This can have a positive impact on the management of patients with superficial tumours that may be resistant to low fractional doses of radiation. Radiofrequency fields modulate cellular radiosensitivity in a frequency- and cell type-dependent manner and their effects appear to be linked to p53 status. Cellular responses such as metabolism, DNA damage processing (based on micronuclei formation), and abnormal proliferation (based on binucleation) seem to be underlying factors mediating the radiomodulatory effects of radiofrequency fields. Mechanisms by which radiofrequency fields can possibly modulate radiosensitivity are: amplification of radiation-induced genotoxicity, cell cycle arrest, and disturbance of other cellular biochemical processes that lead to alteration of homeostasis. Alternative ways by which RFF affect radiosensitivity are: interfering with the synthesis and function of charged proteins in the cell leading to programmed cell death or premature cell ageing, perturbation of intracellular calcium ions which can trigger apoptotic or necrotic cell death, and/or modulating the expression of Bcl-2 family proteins. Given this complexity, a potential use of radiofrequency fields as a non-invasive therapeutic modality would require standardisation to establish reproducibility. A more detailed understanding of how radiofrequency fields interact with ionising radiation would also prove beneficial in the broader field of radiation protection.
Radiosensitisation of androgen-dependent and independent tumour cells as a therapeutic strategy in prostate cancer
(Stellenbosch : Stellenbosch University, 2019-12) Maleka, Sechaba; Akudugu, J. M.; Serafin, A. M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiobiology.
ENGLISH SUMMARY : Metastatic prostate cancer continues to be a leading cause of cancer-related death in men. Increased incidences and mortality have been reported globally, although treatment of locally confined prostate cancer has been shown to be successful. However, aggressive and incurable castration-resistant prostate cancer (CRPC) is a major clinical concern. The combination of radiotherapy and androgen deprivation therapy (ADT) is the current standard-of-care treatment strategy for prostate cancer (PCa). The androgendependent stage of tumour is successfully managed, until the cancer switches to androgen-independence when resistance to treatment severe. The mechanism underlying this switch is still not clear and poorly understood. However, the implicated survival pathways of PI3K/mTOR, EGFR and AR might help explain remissions of PCa after treatment. Thus, the rationale for this study was to target these pathways with respective inhibitors, namely, MDV3100 (for AR), AG-1478 (for EGFR), and NVPBEZ235 (for PI3K and mTOR). The “traditional” prostate cancer cell lines, (DU145 and LNCaP), which are derived from metastatic regions, and (1542N and BPH-1) from normal tissue and a primary benign tumour, respectively, served as biological models in this research. The following were investigated: (1) androgen sensitivity of cell lines, (2) the intrinsic cellular radiosensitivity, (3) the cytotoxicity of specific inhibitors of AR, EGFR, PI3K and mTOR, (4) interaction of the respective inhibitors, and (5) the radiomodulatory effects of inhibitors, either singly or in combination. The “classical” androgen-independent cell lines were found to switch into androgendependence when treated with high concentrations of 5α-DHT. Very strong synergistic interactions of inhibitors were demonstrated in all cell lines, except the LNCaP cell line in which inhibitors were antagonistic. Concomitant use of these inhibitors in intrinsically androgen-dependent prostate cancers might not be beneficial. The use of inhibitor cocktails with radiation at low doses (2 Gy) is highly desirable as the normal cells were protected, especially with the dual inhibitor of PI3K/mTOR (NVP-BEZ235). However, at higher doses (6 Gy) the potential benefit is great in tumour cell lines, but very limited in the normal cell line. Therefore, at fractional doses of relevance to conventional radiotherapy, use of cocktails containing the PI3K/mTOR inhibitor as an adjuvant may be beneficial in the management of androgen-dependent cancer. It is concluded that these findings might assist in the design of more effective treatment approaches for cancers that typically display resistance to radiotherapy and chemotherapy.

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