antifungal therapy could interfere with Rituxan

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Cancer Res. 2010 May 11.

Antifungal Therapy with Itraconazole Impairs the Anti-Lymphoma Effects of

Rituximab by Inhibiting Recruitment of CD20 to Cell Surface Lipid Rafts.

Ringshausen I, Feuerstacke Y, Krainz P, den Hollander J, Hermann K, Buck A,

Peschel C, Meyer Zum Bueschenfelde C.

Authors' Affiliations: Third Medical Department and Department of Nuclear

Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich,

Germany.

Abstract

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 anti-lymphoma 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-raft-associated 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); OF1-5. ©2010 AACR.

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~ Karl

Patients Against Lymphoma

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