Development of rituximab-resistant B-NHL clones: an in vitro model for studying tumor resistance to monoclonal antibody-mediated immunotherapy.

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.

• Authors: Ali R Jazirehi, Benjamin Bonavida
• Journal: Methods in molecular biology (Clifton, N.J.) (Methods Mol Biol) Vol. 731 Pg. 407-19 ( 2011) ISSN: 1940-6029 [Electronic] United States
• PMID: 21516425 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• STAT3 Transcription Factor
• Rituximab
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases

Topics

• Acquired Immunodeficiency Syndrome (complications)
• Animals
• Antibodies, Monoclonal, Murine-Derived (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Clone Cells (drug effects, metabolism, pathology)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunotherapy
• Lymphoma, B-Cell (complications, genetics, pathology, therapy)
• Lymphoma, Follicular (drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NF-kappa B (metabolism)
• Phenotype
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rituximab
• STAT3 Transcription Factor (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)