Radioimmunotherapy of B-cell lymphoma: approach to enhance apoptotic cell death

Radioimmunotherapy (RIT) is a branch of nuclear medicine wherein antibodies are employed to deliver cytotoxic dose of beta/alpha radiation to the targeted sites. The promising therapeutic results of Bexxar® and Zevalin® in lymphoma provide reasonable anticipations for effectiveness of RIT. Benefit of RIT is not only limited to its particulate nature of radiation but it can also target and treat tumor metastases and effectively kill the radioresistant hypoxic cells. Lymphomas are a heterogeneous group of hematological malignancies, affecting mostly B-cells. There are several therapeutic modalities for B cell malignancies. Even though, rituximab is an immunotherapeutic agent used for treatment of NHL patients, only 50% patients showed clinical response. To enhance cell killing rituximab was tagged with beta emitting radionuclide and further expected to increase by pretreatment of chemotherapeutic drugs such as doxorubicin/camptothecin. Raji cells were pretreated with drugs followed by incubation with ¹³¹I- rituximab and various parameters were assessed to study magnitude of apoptosis and lurking mechanism of cell death. Apoptotic cell death was highest in combination of camptothecin/doxorubicin compared to rituximab/¹³¹I- rituximab alone. Raji cells undergo G1 arrest upon ¹³¹I- rituximab treatment, which might be the cause of apoptosis, confirmed by downregulation of bcl_xl and cleavage of PARP. Expressions of p38 MAPK were decreased in combination treatment of camptothecin/doxorubicin and ¹³¹I- rituximab however, phosphorylation of p38 increased. These studies conclude that camptothecin/doxorubicin in combination with ¹³¹I- rituximab enhanced apoptotic cell death in B-cell lymphoma tumor cells which might be the efficacious treatment modality for the lymphoma patients in general. (author)