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Title: Mining dopaminergic pathways for novel therapeutic approaches to non-hodgkin's lymphoma
Author: Wasik, Agata Magdalena
ISNI:       0000 0004 2726 5535
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2009
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This thesis investigates the expression of dopaminergic constituents within human B lymphocytes and selected malignancies thereof while addressing the impact of chemically modifying a structural analogue of dopamine - 3,4-methylenedioxymethamphetamine (MDMA) - on its anti-neoplastic potential. With regards the former, it was concluded that B cells are 'dopaminoceptive' in character rather than dopaminergic. Thus while transcripts for the D2 receptor (D2R) and dopamine transporter (DAT) were expressed, mRNA for dopamine-synthesising tyrosine hydroxylase was undetectable amongst B cells studied. Upon B-cell activation, the D2R and DAT transcripts were translated into readily detectable protein. There was evidence for different D2R isoforms being expressed which, in model B-cell lines, were shown to be localised intracellularly. The recently identified trace amine-associated receptor 1 (Taarl) associated with dopaminergic signalling in the central nervous system was also found expressed at the protein level in human B cells. B-cell Taarl was functional: selective agonists triggering apoptosis in susceptible lines at the low micromolar level. MDMA has been reported to promote apoptosis in susceptible malignant B-cell lines such as those derived from Burkitt's lymphoma. Unfortunately, concentrations required to elicit killing were at least lOO-fold higher than those that could be reached safely in vivo leading to the study herein on analogues of the parental compound iteratively modified at the a-carbon andlor nitrogen site. Modifications resulting in increased potency were indeed found and attempts to unravel mechanisms-of-action of the more potent analogues were begun. The dopaminoceptive system of B cells and their pathologies may therefore offer novel therapeutic opportunities.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available