Glioblastoma Multiform (GBM) is the most common lethal cancer within the central nervous system, accounting for 51% of all gliomas, with a median patient survival between 12 and 14 months post diagnosis. Current treatments employed on patients include surgery, radiotherapy and temozolomide, however with the chemotherapeutic and radiation regimes, an accumulation of resistance to treatments often develops in patients due to the cancers heterogeneous nature. Repurposing of drugs is a novel approach to targeting GBM, with several studies and clinical trials reporting promising effects of use of the anti-alcoholism drug disulfiram in combination with temozolomide, and also the use of multiple sclerosis treatment dimethyl fumarate incombination with temozolomide. The aims of this study were to investigate the cytotoxic effect of fixed regressive ratio combinations of treatments on the human GBM cell line U87 cells for assessing combination synergism through combination index analysis. The study also aimed to characterise the U87 cellline response to the combination models through an array of mechanistic assay cascades. Fixed regressive ratio models of combinations were formulated utilising IC50 values from single agent clonogenic assays as the highest combination concentration ratio. Characterisation of the U87 cells under combination treatment was assessed through changes in cell cycle distribution, dynamics of DNA double stranded break formation and repair by γ-H2AX assays and apoptotic cell population changes by Annexin V assays. This study has characterised combinations of DMF and DSF, TMZ and DSF, and TMZ and DMF on the U87 cell line. Significant cytotoxicity was observed with each single agent and each combination against the control. Mechanistic assays for each combination did not show any significant enhancement of cell cycle arrest or apoptosis instigation, but observed significant changes in response to DNA damage under combinations of TMZ and DSF, and TMZ and DMF against the control. Combination TMZ and DSF also showed the most synergism of the 3 combinations examined, with the higher 3 concentrations in the model observing a synergistic effect on the U87 cells by combination index analysis. Whereas this synergistic relationship was seen at the lowest concentration of DMF and DSF and only at the highest concentrations for TMZ and DMF, therefore showing TMZ and DSF to have the greatest potential for further analysis into combination treatments for glioblastoma.
Date of Award | 1 Jun 2018 |
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Original language | English |
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Awarding Institution | - University Of Strathclyde
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Supervisor | Alexander Mullen (Supervisor) & Marie Boyd (Supervisor) |
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