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Non-absorbable iron chelators for the treatment of colorectal cancer

Byravan, Rama (2015)
Ph.D. thesis, University of Birmingham.

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There is growing epidemiological and experimental evidence implicating excess luminal iron in the context of colorectal cancer. High levels of dietary iron is thought to aid carcinogenesis, due to the formation of reactive oxygen species from the redox cycling of iron, which can cause oxidative tissue damage and disrupt cellular signalling pathways. Hence, it is proposed that removal of this excess iron will suppress the development of this cancer.
A clinically used iron chelator deferasirox and a modified version of this ligand, were attempted to be conjugated onto biopolymers chitosan and alginate. These non-absorbable polymers were hypothesised to be undigested in the gastrointestinal tract, thus specifically capable of targeting and removing excess iron from the colon. These chelator incorporated polymer materials, be they conjugated polymers or functional material blends, were subsequently shown to have improved iron binding properties compared to the parent polymers. Culturing RKO colorectal cancer cells with iron and alginate-ligand material did not significantly affect intracellular iron uptake, however culturing RKO cells with iron and chitosan-ligand material elicited a suppression in iron mediated ferritin expression and overall intracellular iron status. Based on these \(in\) \(vitro\) results, that the material obtained from reaction of chitosan with ligand elicits the desired inhibition of iron uptake, the chitosan-ligand material was administered to a mouse model of colorectal cancer. Apc Hom Pten Hom mice show reduced mitosis and increased apoptosis of intestinal crypt cells, demonstrating anti-neoplastic activity by iron chelation.

Type of Work:Ph.D. thesis.
Supervisor(s):Fossey , John and Teslepis, Chris
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemistry
Subjects:QD Chemistry
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:6403
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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