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Postimmunization with IFN--Secreting Glioma Cells Combined with the Inducible Nitric Oxide Synthase Inhibitor Mercaptoethylguanidine Prolongs Survival of Rats with Intracerebral Tumors¹

Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, University of Lund, Lund, Sweden

High-grade gliomas are one of the most aggressive human tumors with <1% of patients surviving 5 years after surgery. Immunotherapy could offer a possibility to eradicate remnant tumor cells after conventional therapy. Experimental immunotherapy can induce partial cure of established intracerebral tumors in several rodent models. One reason for the limited therapeutic effects could be immunosuppression induced by both the growing tumor and the induced immune reaction. NO has been implicated in tumor-derived immune suppression in tumor-bearing hosts, and unspecific inhibitors of NO synthase have been shown to boost antitumor immunity. In this study, we show that the inducible NO synthase (iNOS)-specific inhibitor mercaptoethylguanidine (MEG) superiorly enhanced lymphocyte reactivity after polyclonal stimulation compared with the iNOS-specific inhibitor L-NIL and the unspecific NO synthase inhibitor L-NAME. Both iNOS inhibitors increased the number and proliferation of T cells but not of B cells. When combined during postimmunization with IFN--secreting N32 rat glioma cells of rats harboring intracerebral tumors, only MEG increased the cure rate. However, this was only achieved when MEG was administered after immunizations. These findings implicate that NO has both enhancing and suppressive effects after active immunotherapy.

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.

¹ This work was supported by grants from The Child Cancer Foundation, The Jonas Foundation, The Hedvig Foundation, The Skåne Regional Funds, and the Gunnar Nilsson Cancer Foundation. Support was also from the Swedish Cancer Foundation and the Hans and Märit Rausing Charitable Foundation.

² Address correspondence and reprint requests to Dr. Wiaam Badn, Division of Neurosurgery, Department of Clinical Sciences, BMC:I12, University of Lund, SE-221 84 Lund, Sweden. E-mail address: wiaam.badn{at}med.lu.se

³ Abbreviations used in this paper: MEG, mercaptoethylguanidine; iNOS, inducible NO synthase; i.c., intracerebral; SEA, staphylococcal enterotoxin A; DCLN, deep cervical lymph node.