title: Low-dose fludarabine increases rituximab cytotoxicity in B-CLL cells by triggering caspases activation in vitro.
abstract: Rituximab maintenance therapy provides a significant benefit in patients with indolent B-cell non-Hodgkin lymphoma (NHL). Based on its efficacy in improving response to chemotherapy, the anti-CD20 antibody is currently under evaluation as maintenance therapy also in patients with B-CLL. We evaluated rituximab-mediated cytotoxicity in 10 B-CLL cases pretreated in vitro with non-cytotoxic concentrations of fludarabine. This combination induced a synergic cytotoxic effect in 8 out of 10 patients at a mean level of 26.15 +/- 13.9%, compared to 8.05 +/- 5.3% cytotoxicity observed with rituximab alone. Consistent with the viability assay, we found an increased caspase-3 activity together with activation of caspase-9 in B-CLL cells sensitive to sequential non-cytotoxic fludarabine and rituximab exposure. Non-cytotoxic fludarabine concentrations may sensitize B-CLL cells to rituximab-mediated cytotoxicity via caspase-3 activation.
authors.affiliation: Department of Internal Medicine, Haematology Unit, Ca' Foncello Hospital, Treviso, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Furlan
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.forename: Francesco
authors.initials: F
authors.lastname: Pietrogrande
authors.forename: Marilena
authors.initials: M
authors.lastname: Celadin
authors.forename: Mariella
authors.initials: M
authors.lastname: Sanzari
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vianello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000096:biosynthesis; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D002469:Cell Separation; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D053148:Caspase 3; D053453:Caspase 9; D014740:Vidarabine; C024352:fludarabine