Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma
Rituximab, the chimeric monoclonal antibody targeting CD20, forms the cornerstone of therapy for diffuse large B-cell lymphoma (DLBCL). However, more than one-third of patients eventually become unresponsive or resistant to rituximab. Although the mechanisms of action and resistance are not well und...
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| Format: | Final Year Project (FYP) |
| Language: | English |
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Nanyang Technological University
2021
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| Online Access: | https://hdl.handle.net/10356/149717 |
| _version_ | 1826119624300691456 |
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| author | Ong, Charmaine Zi Yan |
| author2 | - |
| author_facet | - Ong, Charmaine Zi Yan |
| author_sort | Ong, Charmaine Zi Yan |
| collection | NTU |
| description | Rituximab, the chimeric monoclonal antibody targeting CD20, forms the cornerstone of therapy for diffuse large B-cell lymphoma (DLBCL). However, more than one-third of patients eventually become unresponsive or resistant to rituximab. Although the mechanisms of action and resistance are not well understood, it is postulated that complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity, and apoptosis mediates rituximab’s anti-tumor activity, of which CDC is commonly regarded as the main activity of rituximab in vitro.
We investigated whether drugs often used in combination with rituximab affect CDC and discovered that etoposide, a chemotherapy drug, induces resistance in SU-DHL-4 cells. Using a robust rituximab-induced CDC assay, we performed a screen to identify compounds that might increase CDC when administered together with etoposide. It was found that combination with histone deacetylases (HDAC) and Chk1 inhibitors enhanced CDC in vitro. Most interestingly, preliminary data suggests that these compounds mediate CDC in a CD20-independent manner, which is uncommon among methods to overcome CDC resistance.
In conclusion, etoposide induces resistance to CDC that is alleviated by HDAC and Chk1 inhibitors, possibly through a CD20-independent pathway. These results suggest the potential of HDAC and Chk1 inhibitors as candidate drugs to improve DLBCL treatment. |
| first_indexed | 2024-10-01T05:03:28Z |
| format | Final Year Project (FYP) |
| id | ntu-10356/149717 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:03:28Z |
| publishDate | 2021 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/1497172023-02-28T18:07:12Z Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma Ong, Charmaine Zi Yan - School of Biological Sciences Cancer Science Institute of Singapore Anand Jeyasekharan csiadj@nus.edu.sg Science::Biological sciences Rituximab, the chimeric monoclonal antibody targeting CD20, forms the cornerstone of therapy for diffuse large B-cell lymphoma (DLBCL). However, more than one-third of patients eventually become unresponsive or resistant to rituximab. Although the mechanisms of action and resistance are not well understood, it is postulated that complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity, and apoptosis mediates rituximab’s anti-tumor activity, of which CDC is commonly regarded as the main activity of rituximab in vitro. We investigated whether drugs often used in combination with rituximab affect CDC and discovered that etoposide, a chemotherapy drug, induces resistance in SU-DHL-4 cells. Using a robust rituximab-induced CDC assay, we performed a screen to identify compounds that might increase CDC when administered together with etoposide. It was found that combination with histone deacetylases (HDAC) and Chk1 inhibitors enhanced CDC in vitro. Most interestingly, preliminary data suggests that these compounds mediate CDC in a CD20-independent manner, which is uncommon among methods to overcome CDC resistance. In conclusion, etoposide induces resistance to CDC that is alleviated by HDAC and Chk1 inhibitors, possibly through a CD20-independent pathway. These results suggest the potential of HDAC and Chk1 inhibitors as candidate drugs to improve DLBCL treatment. Bachelor of Science in Biological Sciences 2021-06-09T03:04:39Z 2021-06-09T03:04:39Z 2021 Final Year Project (FYP) Ong, C. Z. Y. (2021). Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma. Final Year Project (FYP), Nanyang Technological University, Singapore. https://hdl.handle.net/10356/149717 https://hdl.handle.net/10356/149717 en application/pdf Nanyang Technological University |
| spellingShingle | Science::Biological sciences Ong, Charmaine Zi Yan Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title | Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title_full | Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title_fullStr | Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title_full_unstemmed | Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title_short | Modulators of rituximab-induced complement-dependent cytotoxicity in diffuse large B-cell lymphoma |
| title_sort | modulators of rituximab induced complement dependent cytotoxicity in diffuse large b cell lymphoma |
| topic | Science::Biological sciences |
| url | https://hdl.handle.net/10356/149717 |
| work_keys_str_mv | AT ongcharmaineziyan modulatorsofrituximabinducedcomplementdependentcytotoxicityindiffuselargebcelllymphoma |