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Title: Drug resistance mechanisms in multiple myeloma
Author: Scott, F. M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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The aim of this thesis was to investigate expression of putative drug resistance markers in myeloma both by examining clinical material and through the development of a xenograft model. Pgp expression was examined in 57 samples from 37 patients with myeloma. Of 23 samples at presentation and 37 at relapse, 7 and 26 respectively were Pgp positive. A myeloma xenograft model was established to examine the acute effects of cytotoxic drugs on the expression of "classical" drug resistance markers and genes involved in regulation of apoptosis. The untreated xenografts were Pgp negative, expressed low levels of glutathione S-transferase-P (GSTP) and had readily detectable topo I and II. Little p62 myc or p53 were detected, whereas bcl-2 was strongly expressed. Treated xenografts contained only scattered apoptotic cells, but the majority demonstrated cell cycle arrest at the G2/M transition, and GSTP and topo IIα expression were increased. Pgp expression was also increased in animals treated on 3 consecutive days. C-myc was detected in dead or dying cells, but there was no mutational inactivation of p53, and bcl-2 expression was unaltered. The increased Pgp and GSTP expression following therapy, rather than inducing a resistant phenotype, may reflect activation of expression by drug administration. Cellular resistance occurred despite evidence of DNA damage suggesting that resistance arose from failure to engage apoptosis, possibly due to the strong bcl-2 expression. Bcl-2 expression was therefore evaluated in 40 samples from 31 individuals, with strong expression observed in over 80% of cases. This was not associated with rearrangement of the bcl-2 locus. The presence of abundant bcl-2 protein in the majority of cases has potentially important implications for drug resistance in this disease and suggests that future assessment of drug resistance in myeloma may be better directed downstream of immediate drug-target interactions to regulation of engagement of apoptosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available