Nitric oxide (NO) signaling in
tumors and endothelial cells regulates vascular permeability and blood flow and therefore influences
tumor uptake and response to therapeutic compounds. As delivery and efficacy of
chemotherapy is impaired in
CNS neoplasms due to a partially intact blood-brain barrier (BBB), we studied the effects of NO released by the short-acting NO donor disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate methanolate (
PROLI/NO) on BBB integrity and blood flow in C6
gliomas using [¹⁴C]-aminoisobutyric
acid (AIB) and [¹⁴C]-
iodoantipyrine quantitative autoradiography.
PROLI/NO selectively increased intratumoral uptake of [¹⁴C]AIB and [¹⁴C]
sucrose when given as a 3-minute intracarotid infusion or a 15-minute i.v. infusion (AIB:
tumor, K₁ = 68.7 ± 3.2 vs 24.9 ± 0.9 µL g⁻¹ min⁻¹, P < .0001;
sucrose, K₁ = 16.9 ± 0.9 vs 11.5 ± 0.9 µL g⁻¹ min⁻¹, P = .0007). This effect was achieved without significant changes in cerebral and
tumor blood flow or arterial blood pressure, which indicates that the effect on vascular permeability is independent of changes in vascular tone induced by NO. This effect was mediated by activation of the NO/3',5'-cyclic
guanosine monophosphate (cGMP) pathway, as it was blocked by
guanylate cyclase inhibition by
LY83583 and reproduced by the delivery of
8-bromoguanosine 5'-monophosphate or inhibition of cGMP degradation by the
phosphodiesterase inhibitor zaprinast. Inhibition of inducible
NO synthase by
aminoguanidine or
cyclooxygenase inhibition by
indometacin or
dexamethasone did not reduce the blood-
tumor barrier (BTB) response to
PROLI/NO.
PROLI/NO, and perhaps other NO-donating compounds, can be used to selectively increase BTB permeability in
gliomas through the NO/cGMP pathway at doses that do not cause unwanted vasodilatory changes in blood flow and that do not affect the systemic circulation.