Radiobiology

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Browsing Radiobiology by browse.metadata.advisor "Serafin, Antonio M."

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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.