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 |
| Language: | English |
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Nanyang Technological University
2021
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| Online Access: | https://hdl.handle.net/10356/149717 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | 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. |
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