Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas

Preliminary clinical trials suggest that iodine-131 (I-131)-labeled anti-CD20 monoclonal antibodies (MAbs) are effective single agents for the treatment of relapsed non-Hodgkin's B-cell lymphomas, However, despite high initial response rates, most patients treated in this manner will eventually relapse. We hypothesized that regimens combining I-131-anti-CD20 antibodies with standard chemotherapeutic agents may provide synergistic anti-tumor effects, and may improve the durability of responses in patients with lymphoma, To identify promising agents for clinical testing, we assessed the in vitro cytotoxicity of combinations of I-131-anti-BI (anti-CD20) antibody and 8 chemotherapeutic agents using 2 human CD20-expressing lymphoma cell lines and 2 corroborative assays, the thiazolyl tetrazolium bromide (MTT) and the Trypan blue dye exclusion assays. ID50 isobolographic and dose modification factor (DMF) analyses were used to classify interactions between the I-131-anti-BI antibody and the chemotherapeutic agents as supra-additive (synergistic), additive or sub-additive. Cytarabine and fludarabine were markedly supra-additive when combined with the radioimmunoconjugate, with the combination enhancing cytotoxiciy 3.5- to 5.2-fold over the level expected by simple addition of the 2 agents (DMFs 3.5-5.2). Etoposide, doxorubicin and SN-38 were moderately supra-additive (DMFs 2.0-2.8). Cisplatin and 4-hydroxycyclophosphamide exhibited merely additive cytotoxicity(DMFs 1.0-1.1), Thus, combination regimens containing I-131-labeled anti-CD20 antibodies and nucleoside analogs or topoisomerase inhibitors appear particularly attractive for future clinical trials. (C) 2000 Wiley-Liss, Inc.