| dc.description.abstract | Discovery of Novel Molecular and Biochemical Predictors
of Response and Outcome in Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the commonest form of non-Hodgkin
lymphoma and responds to treatment with a 5-year overall survival (OS) of 40-50%.
Predicting outcome using the best available method, the International Prognostic Index
(IPI), is inaccurate and unsatisfactory. This thesis describes research undertaken to
discover, explore and validate new molecular and biochemical predictors of response
and long-term outcome with the aims of improving on the inaccurate IPI and of
suggesting novel therapeutic approaches. Two strategies were adopted: a rational and
an empirical approach. The rational strategy used gene expression profiling to identify
transcriptional signatures that correlated with outcome to treatment and from which a
model of 13-genes accurately predict long-term OS. Two components of the 13-gene
model, PKC and PDE4B, were studied using inhibitors in lymphoma cell-lines and
primary cell cultures. PKC inhibition using SC-236 proved to be cytostatic and
cytotoxic in the cell-lines examined and to a lesser extent in primary tumours. PDE4
inhibition using piclamilast and rolipram had no effect either alone or in combination
with chemotherapy. The empirical approach investigated the trace element selenium in
presentation serum and found that it was a biochemical predictor of response and
outcome to treatment. In an attempt to provide evidence of a causal relationship as an
explanation for the associations between presentation serum selenium, response and
outcome, two selenium compounds, methylseleninic acid (MSA) and
selenodiglutathione (SDG) were studied in vitro in the same lymphoma cell-lines and
primary cell cultures. Both MSA and SDG exhibited cytostatic and cytotoxic activity
and caspase-8 and caspase-9 driven apoptosis. For SDG reactive oxygen species
generation was important for its activity in three of the four cell-lines. In conclusion,
molecular and biochemical predictors of response and survival were discovered in
DLBCL that led to viable targets for drug intervention being validated in vitro. | en_US |
