Chemotherapy sensitization by rituximab: experimental and clinical evidence

For most lymphomas, chemotherapy is palliative because of an inability to overcome drug resistance within the lymphoma cells and attempts at overcoming specific drug resistance mechanisms, such as multidrug resistance, have had limited success. However, accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Studies have shown that distinct cellular thresholds exist for apoptosis, and it is likely that multiple developmental and environmental factors converge in a dynamic process to regulate this set point. If the threshold for inducing apoptosis is limiting, then strategies to modulate these pathways may profoundly enhance the efficacy of cytotoxic therapy. Monoclonal antibodies against the CD20 receptor have been shown to directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Recent clinical studies of the monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), and combination chemotherapy have produced unexpectedly high rates of response and progression-free survival, suggesting rituximab improves the efficacy of chemotherapy. Taken together, the results from in vitro and clinical studies suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy.