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Mathematical models characterising the kinetics and dynamics of topotecan to account for drug resistance mechanisms
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Atari, M. I. (Mohammed Isam) (2011) Mathematical models characterising the kinetics and dynamics of topotecan to account for drug resistance mechanisms. PhD thesis, University of Warwick.
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WRAP_THESIS_Atari_2011.pdf - Submitted Version - Requires a PDF viewer. Download (2245Kb) |
Official URL: http://webcat.warwick.ac.uk/record=b2533286~S1
Abstract
This thesis describes the use of mathematical modelling in studying the kinetics and
dynamics of the anti-cancer agent topotecan (TPT), a semi-synthetic derivative of the
natural extract camptothecin (CPT), which has been found to act as an inhibitor of the
DNA enzyme topoisomerase I in a specific and reversible fashion. The drug undergoes
reversible hydrolysis from the pharmacologically active parent lactone form (TPTL) to an
inactive hydroxy acid form (TPTH). In the cytoplasm the irreversible inactivation of TPTL
is catalysed by the enzyme aldehyde dehydrogenase (ALDH). Over-expression of the
human breast cancer resistance protein (BCRP/ABCG2) has been linked to high levels of
resistance to the anti-cancer agent TPT by promoting an active efflux pump mechanism.
The expressions of both ALDH and BCRP have been experimentally identified in a large
number of solid tumours and thus play an important role in clinical drug resistance of
cancers. To investigate the catalytic reaction and efflux pump mechanism, a state-space
model for the in vitro uptake kinetics of TPT has been extended to better describe the drug
activity and delivery of TPTL to the DNA target as well as the catalysis by ALDH and the
elimination of drug from the cytoplasm via the efflux pump. All unknown model
parameters were uniquely estimated to a high level of confidence. Model simulations have
been compared with live human breast cancer cells data and found to give good qualitative
agreement. In addition, a cell cycle model has been extended to include the inhibition
effect of the protein p21CIP1/WAF1 on the cell cycle traverse and the kinetic model has then
been linked to the cell cycle model, which facilitates analysis of the response of the growth
of single cells in the presence and absence of TPT. All unknown model parameters were
uniquely determined by the output structure corresponding to the experiment. Parameter
estimation was performed using green fluorescent protein tagged Cyclin B1 data for the
osteosarcoma cell line U-2 OS. The novel coupling of both models allows the study of drug
perturbation to the cell cycle as well as in silico estimation and prediction of the
relationship between the target binding and the dose, also permitting the effects of different
levels of expression of the drug resistance protein and the ALDH enzyme. Such a coupled
kinetic/dynamic model, once fully validated, has the potential for enhancing the design of
optimal dosing regimens.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QA Mathematics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Library of Congress Subject Headings (LCSH): | Antineoplastic agents -- Mathematical models, Camptothecin -- Analysis, Breast -- Cancer -- Mathematical models | ||||
Official Date: | January 2011 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Engineering | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Evans, Neil D. ; Chappell, Michael John, 1960- | ||||
Sponsors: | University of Warwick | ||||
Extent: | xxii, 265 leaves : ill., charts | ||||
Language: | eng |
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