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Title: Mathematical models characterising the kinetics and dynamics of topotecan to account for drug resistance mechanisms
Author: Atari, Mohammed Isam
ISNI:       0000 0004 2709 1707
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2011
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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.
Supervisor: Not available Sponsor: University of Warwick
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QA Mathematics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)