The response of cancer cells to mitotic kinase inhibitors

  • Claire Aspinall

    Student thesis: Phd


    Around 320,500 people in the UK were diagnosed with cancer in 2009, and more than 1 in 3 people will develop some form of cancer in their lifetime (Cancer Research UK: Together with surgery and radiation therapy, chemotherapy is widely used for the treatment of a range of different cancer types. The majority of chemotherapeutic agents exert their effects by targeting proliferating cells, in most cases by causing DNA damage. However, a second class of agent interferes with the mitotic phase of the cell cycle, by inhibiting microtubule dynamics. These so-called 'anti-mitotics' have been in use for almost two decades, and have contributed to the increase in 5 and 10-year survival rates seen during this time, notably in the cases of breast and ovarian cancer, as well as certain leukaemias. However, our understanding of how these drugs actually lead to patient benefit remains limited. Due to the adverse side effects that can accompany treatment with traditional anti-mitotics, efforts are being made to develop drugs that more specifically target mitosis without affecting microtubules. The mitotic regulatory kinases in particular have received significant attention in recent years. Considerable time, effort and funding has been invested in developing selective and potent mitotic kinase inhibitors, yet so far the clinical trials have been disappointing. Therefore, in order to increase the prospects that these drugs may be useful in the future, it is clear that more in-depth analysis is needed. By defining in more detail how mitotic kinase inhibitors affect cancer cells, it may be possible to identify which types of tumour cells are more likely to respond, and what types of regimens and combinations might be effective.In this thesis I investigate the response of a range of human cancer cell lines to inhibitors of the Aurora and Polo-like kinases, using a single cell-based long-term time-lapse approach. I show that there can be a wide variation in the response of cells to these inhibitors, both within and between cell lines. I then move on to investigate how Plk1 inhibitors can affect the ability of proliferating cells to enter mitosis, and use the data thus obtained to speculate further on the roles of Plk1 in mitotic entry and recovery from the DNA damage checkpoint. The possible implications of these findings for the use of mitotic kinase inhibitors as anti-cancer agents are also discussed.
    Date of Award31 Dec 2013
    Original languageEnglish
    Awarding Institution
    • The University of Manchester
    SupervisorStephen Taylor (Supervisor) & Stephen High (Supervisor)

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