Chimeric Anti-CD20 (IDEC-C2B8) Monoclonal Antibody Sensitizes a B Cell Lymphoma Cell Line to Cell Killing by Cytotoxic Drugs

Abstract

More than 50% of patients with aggressive B lymphomas and the majority of patients with low grade lymphomas are not cured by current therapeutic strategies. The lymphomas express the B cell antigen CD20 on the cell surface and this antigen serves as target for antibody-directed therapies. Clinical studies with encouraging results have been underway with the use of a chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-6 constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8. This study investigated the potential anti-tumor therapeutic value of combination treatment with anti-C2B8 and cytotoxic drugs. The in vitro study examined the sensitizing effect of C2B8 antibody on the DHL-4 B lymphoma line to various cytotoxic agents. Cytotoxicity was determined by the MTT assay. Surface and cytoplasmic proteins were determined by flow cytometry. Pretreatment of DHL-4 with C2B8 resulted in inhibition of cell proliferation and cell death and a fraction of the cells underwent apoptosis. While the DHL-4 tumor cells were relatively resistant to several cytotoxic drugs, pretreatment with C2B8 rendered the cells sensitive to TNF-alpha, ricin, diphtheria toxin (DTX), adriamycin and cisplatin but not to VP-16. Chemosensitization of DHL-4 tumor cells was not due to downmodulation of either the MDR-1 or bcl-2 gene products. However, treatment of DHL-4 with C2B8 inhibited TNF-alpha secretion. These findings demonstrate that C2B8 antibody potentiates the sensitivity of DHL-4 tumor cells to several cytotoxic agents. Further, the findings suggest that combination treatments with C2B8 antibody and drugs may be of clinical benefit in the treatment of patients with resistant aggressive B lymphomas.

Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma

“…Rituximab has been shown to enhance cytotoxicity with cisplatin and overcome resistance to cisplatin and gemcitabine in-vitro (Demidem et al, 1997;Emmanouilides et al, 2002). Combination of rituximab with GEM-P may lead to improved CR rates similar to that seen with rituximab and ICE (Kewalramani et al, 2004).…”

Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies

“…The addition of highly active but nonmyelosuppressive agents may increase CR rates in FC therapy, especially in patients with previously treated CLL, in whom CR rates are reported to remain inadequate. Based on promising in vitro evidence concerning rituximab (anti-CD20 monoclonal antibody) in the sensitization of tumor cell lines to the effects of cytotoxic drugs, 44,45 we have initiated a Phase II study of the combination of fludarabine, cyclophosphamide, and rituximab in the treatment of patients with indolent lymphoid malignancies.…”

Rituximab therapy in malignant lymphoma

“…Finally, evidences that rituximab could synergize with chemotherapeutic agents in B-cell killing were provided by Demidem et al (1997). Subsequent investigations have confirmed synergy of rituximab with fludarabine, doxorubicin and other anticancer drugs (Alas et al, 2000;Alas and Bonavida, 2001;Ghetie et al, 2001).…”