{"id":{"repo_id":"soton","oai_identifier":"oai:eprints.soton.ac.uk:162661"},"canonical_url":"https://search.dev.ndltd.org/etd/soton/oai:eprints.soton.ac.uk:162661","repository":{"repo_id":"soton","name":"University of Southampton","base_url":"https://eprints.soton.ac.uk/cgi/oai2"},"display":{"title":"The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma","abstract":"Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas
have resulted in targeted therapies becoming incorporated into treatment
paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in
dramatic improvements in survival for patients with B cell Non Hodgkin’s
lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer
agents targeting epigenetic regulation.
This thesis addresses the interaction between histone deacetylase inhibitors
and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and
in vivo. The initial approach identified synergistic induction of apoptosis in a
number of B cell lines. In a Ramos xenograft model, combination treatment
with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour
growth compared to either agent alone, without discernable toxicity. This
effect appears specific to CD20 since monoclonal antibodies directed to other
surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.
Analysis of apoptotic pathways demonstrated that PARP cleavage and
caspase processing is significantly higher in cells receiving both treatments.
Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH
abolished the synergy observed with CD20 monoclonal antibodies,
suggesting that caspase processing is necessary for synergy. Treatment of
Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of
synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).
Gene expression array analysis of Ramos cells was performed. Geneset
enrichment analysis identified significant regulation of NF?B target genes in
some genesets (Rituximab Vs control, p<0.001) with a number associated
with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were
confirmed using RT-Q-PCR.
This novel combination elicits the induction of apoptosis in vitro, potentially
through regulation of Bcl-2 family proteins and should be tested in a phase
I/II clinical trial.","abstract_html":"Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas<br/>have resulted in targeted therapies becoming incorporated into treatment<br/>paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in<br/>dramatic improvements in survival for patients with B cell Non Hodgkin’s<br/>lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer<br/>agents targeting epigenetic regulation.<br/><br/>This thesis addresses the interaction between histone deacetylase inhibitors<br/>and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and<br/>in vivo. The initial approach identified synergistic induction of apoptosis in a<br/>number of B cell lines. In a Ramos xenograft model, combination treatment<br/>with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour<br/>growth compared to either agent alone, without discernable toxicity. This<br/>effect appears specific to CD20 since monoclonal antibodies directed to other<br/>surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.<br/>Analysis of apoptotic pathways demonstrated that PARP cleavage and<br/>caspase processing is significantly higher in cells receiving both treatments.<br/>Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH<br/>abolished the synergy observed with CD20 monoclonal antibodies,<br/>suggesting that caspase processing is necessary for synergy. Treatment of<br/>Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of<br/>synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).<br/><br/>Gene expression array analysis of Ramos cells was performed. Geneset<br/>enrichment analysis identified significant regulation of NF?B target genes in<br/>some genesets (Rituximab Vs control, p<0.001) with a number associated<br/>with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were<br/>confirmed using RT-Q-PCR.<br/><br/>This novel combination elicits the induction of apoptosis in vitro, potentially<br/>through regulation of Bcl-2 family proteins and should be tested in a phase<br/>I/II clinical trial.","abstract_has_math":false,"creators":["Nolan, David Francis Luke"],"institution":"University of Southampton","degree_name":"Ph.D.","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Packham, Graham"],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-01","date_published":"2010-01","updated_at":"2026-07-24T04:36:17Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Packham, Graham"]},{"key":"dc:creator","label":"Author","values":["Nolan, David Francis Luke"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-01"]},{"key":"dc:date.issued","label":"Date","values":["2010-01"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Cancer Sciences (pre 2011 reorg)","School of Medicine"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Southampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://eprints.soton.ac.uk/162661/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Ph.D."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://eprints.soton.ac.uk/162661/1/Luke_Nolan_PhD_thesis_final.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas
have resulted in targeted therapies becoming incorporated into treatment
paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in
dramatic improvements in survival for patients with B cell Non Hodgkin’s
lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer
agents targeting epigenetic regulation.
This thesis addresses the interaction between histone deacetylase inhibitors
and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and
in vivo. The initial approach identified synergistic induction of apoptosis in a
number of B cell lines. In a Ramos xenograft model, combination treatment
with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour
growth compared to either agent alone, without discernable toxicity. This
effect appears specific to CD20 since monoclonal antibodies directed to other
surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.
Analysis of apoptotic pathways demonstrated that PARP cleavage and
caspase processing is significantly higher in cells receiving both treatments.
Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH
abolished the synergy observed with CD20 monoclonal antibodies,
suggesting that caspase processing is necessary for synergy. Treatment of
Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of
synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).
Gene expression array analysis of Ramos cells was performed. Geneset
enrichment analysis identified significant regulation of NF?B target genes in
some genesets (Rituximab Vs control, p<0.001) with a number associated
with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were
confirmed using RT-Q-PCR.
This novel combination elicits the induction of apoptosis in vitro, potentially
through regulation of Bcl-2 family proteins and should be tested in a phase
I/II clinical trial."]},{"key":"dc:format","label":"Dc Format","values":["text"]},{"key":"dc:title","label":"Title","values":["The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma"]}]}],"canonical_facts":{"dc:contributor.advisor":["Packham, Graham"],"dc:creator":["Nolan, David Francis Luke"],"dc:date":["2010-01"],"dc:date.issued":["2010-01"],"dc:description.abstract":["Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas
have resulted in targeted therapies becoming incorporated into treatment
paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in
dramatic improvements in survival for patients with B cell Non Hodgkin’s
lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer
agents targeting epigenetic regulation.
This thesis addresses the interaction between histone deacetylase inhibitors
and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and
in vivo. The initial approach identified synergistic induction of apoptosis in a
number of B cell lines. In a Ramos xenograft model, combination treatment
with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour
growth compared to either agent alone, without discernable toxicity. This
effect appears specific to CD20 since monoclonal antibodies directed to other
surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.
Analysis of apoptotic pathways demonstrated that PARP cleavage and
caspase processing is significantly higher in cells receiving both treatments.
Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH
abolished the synergy observed with CD20 monoclonal antibodies,
suggesting that caspase processing is necessary for synergy. Treatment of
Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of
synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).
Gene expression array analysis of Ramos cells was performed. Geneset
enrichment analysis identified significant regulation of NF?B target genes in
some genesets (Rituximab Vs control, p<0.001) with a number associated
with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were
confirmed using RT-Q-PCR.
This novel combination elicits the induction of apoptosis in vitro, potentially
through regulation of Bcl-2 family proteins and should be tested in a phase
I/II clinical trial."],"dc:format":["text"],"dc:identifier.uri":["https://eprints.soton.ac.uk/162661/1/Luke_Nolan_PhD_thesis_final.pdf"],"dc:publisher.department":["Cancer Sciences (pre 2011 reorg)","School of Medicine"],"dc:publisher.institution":["University of Southampton"],"dc:relation.isreferencedby":["https://eprints.soton.ac.uk/162661/"],"dc:title":["The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["Ph.D."]},"updated_at":"2026-07-24T04:36:17Z"}