Abstract
Therapeutic strategies for cancer include chemotherapy, immunotherapy, and radiation. Such therapies result in significant short-term clinical responses; however, relapses and recurrences occur with no treatments. Targeted therapies using monoclonal antibodies have improved responses with minimal toxicities. For instance, Rituximab (chimeric anti-CD20 monoclonal antibody) was the first FDA-approved monoclonal antibody for the treatment of patients with non-Hodgkin’s lymphoma (NHL). The clinical response was significantly improved when used in combination with chemotherapy. However, a subset of patients does not respond or becomes resistant to further treatment. Rituximab-resistant (RR) clones were used as a model to address the potential mechanisms of resistance. In this chapter, we discuss the underlying molecular mechanisms by which rituximab signals the cells and modifies several intracellular survival/antiapoptotic pathways, leading to its chemo/immunosensitizing activities. RR clones were developed to mimic in vivo resistance observed in patients. In comparison with the sensitive parental cells, the RR clones are refractory to rituximab-mediated cell signaling and chemosensitization. Noteworthy, interference with the hyperactivated survival/antiapoptotic pathways in the RR clones with various pharmacological inhibitors mimicked rituximab effects in the parental cells. The development of RR clones provides a paradigm for studying resistance by other anticancer monoclonal antibodies in various tumor models.
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Abbreviations
- 2MAM-A3:
-
2-Methoxyantimycin-A3
- ADCC:
-
Antibody-dependent cell-mediated cytotoxicity
- AP-1:
-
Activator protein-1
- ARL:
-
Acquired immunodeficiency syndrome (AIDS)-related lymphoma
- Bcl-2:
-
B-cell lymphoma protein 2
- Bcl-xL :
-
Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)
- CDC:
-
Complement-dependent cytotoxicity
- DHMEQ:
-
Dehydroxymethylepoxyquinomicin
- DLBCL:
-
Diffuse large B-cell lymphoma
- ERK1/2 MAPK:
-
Extracellular signal-regulated kinase1/2 mitogen activated protein kinase
- FACS:
-
Fluorescence-activated cell sorter
- IKK:
-
Inhibitor of kappa B (IκB) kinase complex
- Mcl-1:
-
Myeloid cell differentiation 1
- RKIP:
-
Raf-1 kinase inhibitor protein
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Jazirehi, A.R., Bonavida, B. (2011). Development of Rituximab-Resistant B-NHL Clones: An In Vitro Model for Studying Tumor Resistance to Monoclonal Antibody-Mediated Immunotherapy. In: Cree, I. (eds) Cancer Cell Culture. Methods in Molecular Biology, vol 731. Humana Press. https://doi.org/10.1007/978-1-61779-080-5_33
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DOI: https://doi.org/10.1007/978-1-61779-080-5_33
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