Modulation of P-glycoprotein by Zosuquidar Trihydrochloride

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