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Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Authors' Affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California

Requests for reprints: Keith L. Black, Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800 East, Los Angeles, CA 90048. Phone: 1-310-423-1773; Fax: 1-310-423-1008; E-mail: keith.black{at}cshs.org.

Purpose: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats.

Experimental Design: The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, K_i, for [¹⁴C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured.

Results: Oral administration of L-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (K_Ca) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/or hydroxyurea.

Conclusions: Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.