Multidrug resistance (MDR) describes the phenomenon whereby cancer cells exposed to a single cytotoxic drug develop cross resistance to numerous other structurally unrelated chemotherapeutics. The development of MDR is a major cause of cancer chemotherapy treatment failure in all types of cancer. Numerous mechanisms of MDR have been elucidated which include ATPbinding cassette (ABC) transporter proteins, cytoplasmic vaults, alterations in topoisomerase II and increased expression of glutathione-S-transferases, all of which result in reduced chemotherapeutic efficacy. Superficial bladder cancer is commonly treated with adjuvant intravesical chemotherapy using mitomycin C or epirubicin (an anthracycline), following surgical resection. However, despite this treatment, the recurrence rates of these tumours can approach 60%. This high recurrence rate represents the development of MDR in many cases. Previous work using anthracycline fluorescence has shown that MDR cells have reduced levels of anthracycline uptake and also demonstrate a characteristic nuclear sparing of drug uptake. This nuclear sparing phenomenon in MDR cells transcends tissue type and suggests that the nuclear membrane may also play a role in MDR. The work described herein discusses the current role of chemotherapy in the treatment of superficial bladder cancer, mechanisms of MDR and the role of the nuclear membrane in MDR. Following this our investigation of the role of the nuclear membrane is described, using a number of novel techniques including cell fusion and microinjection. In addition, we investigated MDR modulation by verapamil, with analysis of changes in cellular, cytoplasmic and nuclear drug uptake mediated by this known MDR reversing agent.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:503138 |
| Date | January 2007 |
| Creators | Featherstone, Jonathan Mark |
| Contributors | Primrose, John ; Cooper, A. |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/67628/ |
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