Cancer Therapy: Preclinical Regulation of CD20 in Rituximab-Resistant Cell Lines and B-cell Non-Hodgkin Lymphoma
نویسندگان
چکیده
Purpose: The aim of this research was to further investigate the contribution of CD20 antigen expression to rituximab activity and define the mechanisms responsible for CD20 downregulation in rituximabresistant cell lines (RRCL). Experimental Design: Rituximab-sensitive cell lines, RRCL, and primary neoplastic B cells were evaluated by chromium-51 release assays, ImageStream image analysis, immunohistochemical staining, flow cytometric analysis, CD20 knockdown, promoter activity, chromatin immunoprecipitation (ChIP) analysis of CD20 promoter, andCD20plasmid transfection experiments to identifymechanisms associated with CD20 regulation in RRCL. Results: RRCL exhibited a gradual loss of CD20 surface expression with repeated exposure to rituximab. We identified a CD20 antigen surface threshold level required for effective rituximab-associated complement-mediated cytotoxicity (CMC). However, a direct correlation between CD20 surface expression and rituximab-CMC was observed only in rituximab-sensitive cell lines. CD20 promoter activity was decreased in RRCL. Detailed analysis of various CD20 promoter fragments suggested a lack of positive regulatory factors in RRCL. ChIP analysis showed reduced binding of several key positive regulatory proteins on CD20 promoter in RRCL. Interleukin-4 (IL-4) induced higher CD20 promoter activity and CD20 expression but modestly improved rituximab activity in RRCL and in primary B-cell lymphoma cells. Forced CD20 expression restored cytoplasmic but not surface CD20, suggesting the existence of a defect in CD20 protein
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Development of DOTA-Rituximab kit formulation to be labeled with 90Y for radioimmunotherapy of B-cell Non-Hodgkin Lymphoma
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NHL is the most common hematologic cancer in adults. Rituximab is the FDA approved treatment of relapsed or refractory low grade B-cell Non-Hodgkin Lymphoma (NHL). But patients eventually become resistant to rituximab. Since lymphocytes and lymphoma cells are highly radiosensitive, low grade NHL that has relapsed or refractory to standard therapy is treated by RIT in which a beta-emitting radio...
متن کاملRegulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma.
PURPOSE The aim of this research was to further investigate the contribution of CD20 antigen expression to rituximab activity and define the mechanisms responsible for CD20 downregulation in rituximab-resistant cell lines (RRCL). EXPERIMENTAL DESIGN Rituximab-sensitive cell lines, RRCL, and primary neoplastic B cells were evaluated by chromium-51 release assays, ImageStream image analysis, im...
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