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¹ INSERM U421, Faculté de Médecine 2^ème étage, Creteil, France; ² Département de pharmacologie, Faculté de Médecine 1^er étage, Creteil, France; ³ Service d'hématologie, Hôpital Henri Mondor, Creteil, France; and ⁴ INSERM U503, Lyon, France

Requests for Reprints:Marc Peschanski, INSERM U421, Faculté de Médecine 2^ème étage, 8 rue du Général Sarrail, 94010 Creteil cedex, France. E-mail: peschanski{at}im3.inserm.fr

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.

Key Words: glioblastoma • GL15 cells • brain slice culture • HIV-protease inhibitors • ritonavir • proteasome inhibitors • anticancer therapies • apoptosis • cytostatic effect • animal

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 7/03; revised 11/ 5/03; accepted 11/13/03.