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Modulation of P-glycoprotein by zosuquidar trihydrochloride.

Gerrard, G.; (2007) Modulation of P-glycoprotein by zosuquidar trihydrochloride. Doctoral thesis , University of London. Green open access

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P-glycoprotein (P-gp), a major contributor in multidrug resistance (MDR), is a cell surface drug efflux pump restricting the intracellular accumulation of many agents used in cancer chemotherapy leading to treatment failure. Over-expression of P-gp is a significant indicator of poor outcome in cancer including acute myelogenous leukaemia (AML). In addition to its primary drug efflux role, P-gp over-expression may also exert a protective influence on a cell's ability to undergo apoptosis in response to certain stimuli. A wide range of P-gp inhibitors have been developed for clinical use in an attempt to modulate the MDR phenotype. Zosuquidar Trihydrochloride (Z.3HCL) is a potent and specific third generation P-gp inhibitor and functions in a non competitive manner. Z.3HCL was the subject of three phase I clinical trials: two on patients with solid tumours and one on 16 patients with AML. Functional and expression assays were conducted on CD56+ NK cells isolated from patients enrolled on these studies. Safety and efficacy data were also analysed, where available. Z.3HCL was also implemented in a number of in vitro assays investigating P-gp expression and function in malignant cells isolated from patients with haematological malignancies: 48 with AML, 75 with CLL, and 16 with MM. Apoptosis assays, utilising normal, patient, and cultured cells were undertaken to investigate the putative role of P-gp in apoptotic modulation. In the solid tumour trials, in vitro assays showed that Z.3HCL infusion was associated with rapid inhibition of P-gp mediated efflux in CD56+ NK cells in 85.2% patients studied. Of the patients enrolled on the AML trial, 11 achieved a complete remission and one a partial remission, with a median survival of 559 (range 38-906) days. Non-haematologic grade 3 and 4 toxicities were observed in four patients. The in vitro assays showed that Z.3HCL infusion was associated with rapid inhibition of P-gp mediated efflux in CD56+ NK cells in all 16 patients, and in CD33+ cells from 6/10 patients. The median IC50 for daunorubicin (DNR) using a MTT assay, decreased significantly between Z.3HCL modulated and unmodulated cells (153 and 247 ng/mL respectively, P=0.01). In vitro studies showed that 38.2% of samples from AML patients, 61.3% from CLL and 41.2% from MM over-expressed P-gp. Drug sensitisation studies on AML cells showed significantly increased drug sensitivity in P-gp positive co- incubated with Z.3HCL and DNR, which was not observed for P-gp negative cells or for co-incubation with cytarabine. Further studies in CLL patients showed that P-gp function and expression did not correlate with other prognostic indicators such as Binet stage, ZAP-70 expression or lgVH mutation status. The intermediately P-gp expressing cell line CEMv showed a significant resistance to ionising radiation compared with CEM cells. Apoptosis assays demonstrated that modulating P-gp with Z.3HCL was able to increase significantly the apoptotic sensitivity above baseline in the highly P-gp expressing CEM-VLB10o cells, an effect not seen in the P-gp negative parent CEM cells.

Type: Thesis (Doctoral)
Title: Modulation of P-glycoprotein by zosuquidar trihydrochloride.
Identifier: PQ ETD:592001
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School
URI: https://discovery.ucl.ac.uk/id/eprint/1444692
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