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  • Title: Rituximab-mediated chemosensitization of AIDS and non-AIDS non-Hodgkin's lymphoma.
    Author: Bonavida B, Vega MI.
    Journal: Drug Resist Updat; 2005; 8(1-2):27-41. PubMed ID: 15939340.
    Abstract:
    Patients with B non-Hodgkin's Lymphoma (NHL) initially respond to conventional chemotherapy. However, relapses and recurrences occur and the patients develop resistance to further treatment. Immunotherapeutic approaches have been considered in the treatment of such patients. Rituximab (chimeric anti-human CD20 monoclonal antibody) is the first anti-cancer monoclonal antibody approved by the FDA for the treatment of B-NHL. It has been used alone or in combination with chemotherapy, and the clinical response rates have been 50% and greater than 95%, respectively. The in vivo mechanism by which rituximab mediates its effects is not clear, though ADCC, CDC and apoptosis have been suggested and supported by several studies. However, many patients do not respond to rituximab or become refractory to rituximab treatment and the underlying mechanism of unresponsiveness is not known. This review describes various molecular signaling pathways modified by rituximab using in vitro B-NHL cell lines as model systems. The findings demonstrate that rituximab treatment modulates the p38 MAPK, the Raf-1/MEK/ERK1/2 and the NF-kappaB pathways. These modifications induced by rituximab were in large part responsible for the down-regulation of the anti-apoptotic gene products Bcl-2/Bcl-xL and chemosensitization of the drug-resistant B-NHL cell lines to various drug-induced apoptosis. Studies on the development of resistance to rituximab were investigated with rituximab-resistant B-NHL clones derived from rituximab-sensitive B-NHL cell lines. The molecular signaling pathways modified by rituximab revealed several novel intracellular targets whose modification could sensitize both rituximab-sensitive and rituximab-resistant B-NHL to drug-induced apoptosis. These in vitro findings provide new possibilities for improving the clinical effectiveness of rituximab as well as for circumventing its resistance.
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