Mechanisms of multidrug resistance in bladder cancer: the role of the nuclear membrane

Multidrug resistance (MDR) describes the phenomenon whereby cancer cells<br/>exposed to a single cytotoxic drug develop cross resistance to numerous other<br/>structurally unrelated chemotherapeutics. The development of MDR is a major<br/>cause of cancer chemotherapy treatment failure in all types of cancer.<br/><br/>Numerous mechanisms of MDR have been elucidated which include ATPbinding<br/>cassette (ABC) transporter proteins, cytoplasmic vaults, alterations in<br/>topoisomerase II and increased expression of glutathione-S-transferases, all of<br/>which result in reduced chemotherapeutic efficacy.<br/><br/>Superficial bladder cancer is commonly treated with adjuvant intravesical<br/>chemotherapy using mitomycin C or epirubicin (an anthracycline), following<br/>surgical resection. However, despite this treatment, the recurrence rates of<br/>these tumours can approach 60%. This high recurrence rate represents the<br/>development of MDR in many cases.<br/><br/>Previous work using anthracycline fluorescence has shown that MDR cells<br/>have reduced levels of anthracycline uptake and also demonstrate a<br/>characteristic nuclear sparing of drug uptake. This nuclear sparing<br/>phenomenon in MDR cells transcends tissue type and suggests that the<br/>nuclear membrane may also play a role in MDR.<br/><br/>The work described herein discusses the current role of chemotherapy in the<br/>treatment of superficial bladder cancer, mechanisms of MDR and the role of the<br/>nuclear membrane in MDR. Following this our investigation of the role of the<br/>nuclear membrane is described, using a number of novel techniques including<br/>cell fusion and microinjection. In addition, we investigated MDR modulation by<br/>verapamil, with analysis of changes in cellular, cytoplasmic and nuclear drug<br/>uptake mediated by this known MDR reversing agent.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2007

Author dc:creator

• Featherstone, Jonathan Mark

Advisors dc:contributor.advisor

• Primrose, J.
• Cooper, A.