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    Preclinical evaluation of pharmacological strategies designed to enhance the activity of established and novel anti-cancer drugs. Synopsis: Evaluation of pharmacological strategies designed to modulate the Warburg effect, enhance the activity of tyrosine kinase inhibitors and novel analogues of Temozolomide.

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    PhD Thesis (3.801Mb)
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    Publication date
    2014
    Author
    Saleem, Mohammed Umer
    Supervisor
    Phillips, Roger M.
    Pors, Klaus
    Keyword
    Warburg effect; Glutamine metabolism; Tyrosine kinase inhibitors; Dichloroacetate; Pyruvate dehydrogenase kinase; Temozolomide; Chemosensitivity
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Institute of Cancer Therapeutics
    Awarded
    2014
    
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    Abstract
    Whilst progress has been made in reducing mortality in some cancers, mortality rates remain high in many cancers and there is a need to develop novel therapeutic strategies. In this thesis, various pharmacological strategies designed to enhance the activity of existing therapeutic drugs were evaluated. Cancer cells are dependent upon aerobic glycolysis (the Warburg effect) and glutamine uptake. Using clinically approved tyrosine kinase inhibitors and Bortezomib, significant enhancement of chemosensitivity was observed when used in combination with inhibitors of lactate dehydrogenase (Gossypol) and pyruvate kinase dehydrogenase (Dichloroacetate). In contrast, depletion of glutamine from media had to be extensive in order to induce cell death and cell death only occurred after prolonged exposure to glutamine-deprived conditions. This suggests that glutamine depletion strategies alone are unlikely to be successful but may be useful in combination with other agents targeting glutamine addiction in cancer cells. Finally, Temozolomide (TMZ) is an important drug in the treatment of glioblastomas but its activity is reduced by resistance mechanisms including O6 methyl guanine methyltransferase (MGMT) and mismatch repair (MMR). This thesis has identified analogues of TMZ (EA02-45, EA02-59, EA02-64 and EA02-65) that are MGMT and MMR independent in terms of inducing cell kill in vitro. These compounds are promising leads for future development. In conclusion, this thesis has demonstrated that interfering with the metabolic phenotype of cancer can enhance the activity of existing drugs and identified novel analogues of TMZ that circumvent drug resistance mechanisms that hamper the efficacy of TMZ.
    URI
    http://hdl.handle.net/10454/13842
    Type
    Thesis
    Qualification name
    PhD
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