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Title: Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer
Author: Ball, Patrick
ISNI:       0000 0004 8501 6035
Awarding Body: Bangor University
Current Institution: Bangor University
Date of Award: 2019
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Cancer is one of the leading causes of death worldwide and improving the efficacy of cancer chemotherapy treatments is one of the most pressing issues of the day. Prodrugs hold great promise in that regard as they can be activated selectively, allowing for a more focused treatment strategy than with conventional chemotherapy drugs. Directed enzyme prodrug therapy (DEPT) is a form of cancer chemotherapy that is being developed to utilise prodrugs in combination with prodrug-activating enzymes which would be selectively delivered to a tumour site prior to prodrug administration to allow prodrug activation to occur only at the cancer site. Current DEPT strategies have their own inherent flaws based on the biological methods being used to deliver the prodrug-activating enzymes to the tumour site. Magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT) is a novel approach that is being developed within our research group that seeks to overcome these problems by using gold-coated magnetic nanoparticles as the enzyme delivery system. In this study, the suitability of several enzymes and prodrugs for use in future MNDEPT treatments were tested. The study assessed a range of enzymes including two novel nitroreductases from Bacillus cereus, two Xenobiotic reductases from Pseudomonas putida and two genetically modified nitroreductases previously developed within our research group. The prodrug candidates tested were the heavily investigated nitroreductase prodrug, CB1954, and two forefront dinitrobenzamide mustard prodrugs, PR-104A and SN27686. Several enzyme/prodrug combinations tested were identified as being promising for use in future DEPT treatments, including 1619-his with CB1954, XenB-cys with CB1954 and YfkO-cys with PR-104A. The YfkO-cys/PR-104A combination was of particular promise as it displayed a Michaelis-Menten kinetic efficiency that is nearly three times greater than that shown by the heavily investigated NfnB/CB1954 combination, which displayed limited clinical performance because of the low turnover rate of CB1954 by NfnB. Furthermore, a new method of assessing the ratio of the hydroxylamine products formed from the enzymatic reduction of CB1954 using HPLC has been identified and is reported within this body of work. Building on this, new revelations about how the product ratio changes over time have come to light and this has proven that kinetics-driven changes to the product ratio can occur as the reaction proceeds over time and this is reported here.
Supervisor: Gwenin, Christopher Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Nitroreductase ; Prodrug ; Cancer ; Dept ; HPCC