Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to membrane microdomains. Here, we show that concomitant antifungal treatment with itraconazole impairs the rituximab antilymphoma effect both in vitro and in vivo. At the molecular level, recruitment of CD20 to lipid rafts is inhibited in the presence of itraconazole. Furthermore, calcium influx, which is crucial for rituximab-mediated cell death, was nearly completely abolished by itraconazole treatment. In contrast, the antifungal drug caspofungin did not inhibit CD20 recruitment to lipid rafts, nor did it affect calcium influx or the cytotoxic effect of rituximab. The finding that itraconazole also abolished the cytotoxic effects of other therapeutic antibodies directed against lipid raft-associated molecules (i.e., CD20 and CD52) but not those against the non-raftassociated molecule CD33 further supported our proposed mechanism of action. Our results argue that concomitant medications must be adjusted carefully to achieve optimal antitumor effects with monoclonal antibodies. Cancer Res; 70(11); 4292-6. ©2010 AACR.
2735 Poster Board II-711 Patients with hematologic malignancies have a high risk of developing invasive fungal infections. The higher risk is attributed to host defense impairment due to intensive cytotoxic chemotherapies, hematopoetic stem cell transplantation, and immunosuppressive agents. As early treatment initiation in patients with invasive fungal infections has a profound impact on mortality rates, different antifungal treatment strategies like prophylaxis, empirical, pre-emptive and targeted treatment after proven fungal infection have been developed. Azoles are the most broadly used antifungal drugs inhibiting CYP51. They play a pivotal role in the treatment and prophylaxis of systemic and dermal mycoses. Azoles inhibit the sterol 14a-demethylase activity and block sterol biosynthesis, which is lethal in unicellular organisms. However, in mammalian cells, it has been shown that they lower endogenous cholesterol production. As lipid rafts consist of sphingolipids and cholesterol and lipid rafts have been demonstrated to be crucial for rituximab induced cell death, we asked whether rituximab exhibits its full anti-lymphoma effect in the presence of azoles. We now demonstrate that antifungal treatment with itraconazole impairs rituximab's anti-lymphoma effect both in vitro and in vivo. Using a mouse xenograft model, no tumor growth was observed in mice treated with rituximab. In contrast, in the presence of itraconazole there was tumor growth, indicating that the concentration was sufficient to antagonize rituximab′s anti-lymphoma effect. On the molecular level, CD20 raft recruitment was inhibited in the presence of itraconazole. Furthermore, the translocation of CD20 into lipid rafts has been shown to be crucial for calcium influx and apoptosis. Therefore, we tested the rituximab induced calcium flux in the absence and presence of itraconazole. Indeed, calcium flux was almost completely abolished in the presence of itraconazole. The fact that antibody treatment failure in the presence of itraconazole only affects targeted therapy against raft associated molecules i.e. CD20 and CD52 but not the non raft associated molecule CD33 further supports our proposed mechanism of action. Together, our data suggest that concomitant treatment of itraconazole and rituximab attenuates rituximab's anti-lymphoma effect. As chemotherapy by itself has high response rates in lymphoma, the loss of rituximab mediated cell death in the presence of itraconacole may be missed in our daily routine. Disclosures: No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.