title: Understanding rituximab function and resistance: implications for tailored therapy.
abstract: The addition of anti-CD20 monoclonal antibody (rituximab) to chemotherapy has significantly improved survival in B-cell lymphoma. However, a substantial number of patients relapse after treatment with rituximab. Understanding of anti-CD20 antibody molecular function may facilitate the development of pharmacologic strategies to overcome resistance. Cell death have been demonstrated to be caused by rituximab binding to CD20 throughout direct and indirect mechanisms. The direct mechanism comprises growth inhibition, induction of apoptosis and sensitization of cells to chemotherapy. While, the indirect mechanisms to Rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). However, these mechanisms are still poorly understood. To shed light on this issue, we have analyzed the most significant results showing the role of Rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Mechanisms of resistance to Rituximab are also discussed. Additionally, studies here reported show that, cellular targets are modified after treatment with Rituximab and may become useful for novel therapeutic strategies in the treatment of patients resistant to standard therapy.
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Amoroso
authors.forename: Sameh
authors.initials: S
authors.lastname: Hafsi
authors.forename: Loredana
authors.initials: L
authors.lastname: Militello
authors.forename: Alessia E
authors.initials: AE
authors.lastname: Russo
authors.forename: Zohra
authors.initials: Z
authors.lastname: Soua
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000069283:Rituximab; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D051020:bcl-X Protein / Q000037:antagonists & inhibitors; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; D019014:fas Receptor; D000069283:Rituximab; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases