{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:24:44Z","timestamp":1778718284424,"version":"3.51.4"},"reference-count":49,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,10]]},"abstract":"Object.<\/jats:italic> The response of brain tumors to systemic chemotherapy is limited by the blood\u2014tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli\/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats.<\/jats:p>\nMethods.<\/jats:italic> The Proli\/NO was infused at a wide dose range (10\u22122<\/jats:sup> to 10\u221212<\/jats:sup> M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14<\/jats:sup>C]aminoisobutyric acid, [14<\/jats:sup>C]sucrose, [14C<\/jats:sup>]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli\/NO (10\u22126<\/jats:sup> M) and carboplatin (20 mg\/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli\/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli\/NO and carboplatin, and no toxicity was observed.<\/jats:p>\nConclusions.<\/jats:italic> This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.<\/jats:p>","DOI":"10.3171\/jns.2003.99.4.0728","type":"journal-article","created":{"date-parts":[[2009,5,13]],"date-time":"2009-05-13T17:49:22Z","timestamp":1242236962000},"page":"728-737","source":"Crossref","is-referenced-by-count":41,"title":["Selective opening of the blood\u2014brain barrier by a nitric oxide donor and long-term survival in rats with C6 gliomas"],"prefix":"10.3171","volume":"99","author":[{"given":"Astrid","family":"Weyerbrock","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart","family":"Walbridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryszard M.","family":"Pluta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph E.","family":"Saavedra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry K.","family":"Keefer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward H.","family":"Oldfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"key":"b1","series-title":"J Appl Physiol","first-page":"435","article-title":"Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension.","volume":"84","author":"Adrie","year":"1998"},{"key":"b2","series-title":"J Neurosurg","first-page":"118","article-title":"Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage.","volume":"83","author":"Afshar","year":"1995"},{"key":"b3","series-title":"J Pharmacol Exp Ther","first-page":"903","article-title":"Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival.","volume":"293","author":"Bartus","year":"2000"},{"key":"b4","series-title":"J Pharmacol Exp Ther","first-page":"724","article-title":"Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brain tumors: implications for chemotherapy.","volume":"231","author":"Blasberg","year":"1984"},{"key":"b5","series-title":"Ann Neurol","first-page":"202","article-title":"Regional blood-to-tissue transport in ethylnitrosourea-induced brain tumors.","volume":"14","author":"Blasberg","year":"1983"},{"key":"b6","series-title":"Brain Res","first-page":"75","article-title":"Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis.","volume":"720","author":"Boje","year":"1996"},{"key":"b7","series-title":"J Surg Res","first-page":"26","article-title":"Boundary layer infusion of nitric oxide reduces early smooth muscle cell proliferation in the endarterectomized canine artery.","volume":"67","author":"Chen","year":"1997"},{"key":"b8","series-title":"Microvasc Res","first-page":"35","article-title":"Effects of cyclic GMP on microvascular permeability of the cerebral cortex.","volume":"58","author":"Chi","year":"1999"},{"key":"b9","series-title":"Anesth Analg","first-page":"703","article-title":"Effects of CAS 754, a new nitric oxide donor, on regional cerebral blood flow in focal cerebral ischemia.","volume":"80","author":"Chi","year":"1995"},{"key":"b10","series-title":"Adv Neuroimmunol","first-page":"443","article-title":"Role of nitric oxide in cell-mediated tumor cytotoxicity.","volume":"5","author":"Cifone","year":"1995"},{"key":"b11","series-title":"Neurosurgery","first-page":"270","article-title":"Intra-arterial Cereport (RMP-7) and carboplatin: a dose escalation study for recurrent malignant gliomas.","volume":"44","author":"Cloughesy","year":"1999"},{"key":"b12","series-title":"Cancer Res","first-page":"727","article-title":"Expression of nitric oxide synthase in human central nervous system tumors.","volume":"55","author":"Cobbs","year":"1995"},{"key":"b13","series-title":"Cancer","first-page":"1598","article-title":"Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth.","volume":"77","author":"Doi","year":"1996"},{"key":"b14","series-title":"Cancer","first-page":"637","article-title":"Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors.","volume":"88","author":"Doolittle","year":"2000"},{"key":"b15","series-title":"Br J Cancer","first-page":"964","article-title":"Enhanced delivery of carboplatin into brain tumours with intravenous Cereport (RMP7): dramatic differences and insight gained from dosing parameters.","volume":"80","author":"Emerich","year":"1999"},{"key":"b16","series-title":"Naunyn Schmiedebergs Arch Pharmacol","first-page":"113","article-title":"The use of nitric oxide donors in pharmacological studies.","volume":"358","author":"Feelisch","year":"1998"},{"key":"b17","series-title":"FASEB J","first-page":"1775","article-title":"Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids: implications for the fate of NO in vivo.","volume":"16","author":"Feelisch","year":"2002"},{"key":"b18","series-title":"Neurosurgery","first-page":"199","article-title":"Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model.","volume":"47","author":"Fortin","year":"2000"},{"key":"b19","series-title":"Am J Pathol","first-page":"713","article-title":"Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions.","volume":"150","author":"Fukumura","year":"1997"},{"key":"b20","series-title":"Ann Neurol","first-page":"50","article-title":"Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow.","volume":"19","author":"Hiesiger","year":"1986"},{"key":"b21","series-title":"FASEB J","first-page":"31","article-title":"Endothelium-derived nitric oxide: actions and properties.","volume":"3","author":"Ignarro","year":"1989"},{"key":"b22","series-title":"Proc Natl Acad Sci USA","first-page":"9265","article-title":"Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.","volume":"84","author":"Ignarro","year":"1987"},{"key":"b23","series-title":"J Neurosurg","first-page":"752","article-title":"Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors.","volume":"81","author":"Inamura","year":"1994"},{"key":"b24","series-title":"Proc Natl Acad Sci USA","first-page":"4392","article-title":"Roles of nitric oxide in tumor growth.","volume":"92","author":"Jenkins","year":"1995"},{"key":"b25","series-title":"Am J Physiol","first-page":"H611","article-title":"Nitric oxide modulates microvascular permeability.","volume":"262","author":"Kubes","year":"1992"},{"key":"b26","series-title":"Pflugers Arch","first-page":"654","article-title":"Desensitization of the bradykinininduced rise in intracellular free calcium in cultured endothelial cells.","volume":"412","author":"Luckhoff","year":"1988"},{"key":"b27","series-title":"Anticancer Res","first-page":"299","article-title":"Expression of nitric oxide synthase isozymes (NOS I\u2013III) by immunohistochemistry and DNA in situ hybridization. Correlation with macrophage presence, vascular endothelial growth factor (VEGF) and oedema volumetric data in 220 glioblastomas.","volume":"20","author":"Ludwig","year":"2000"},{"key":"b28","series-title":"J Leukoc Biol","first-page":"588","article-title":"Multiple functions of nitric oxide in pathophysiology and microbiology: analysis by a new nitric oxide scavenger.","volume":"56","author":"Maeda","year":"1994"},{"key":"b29","series-title":"J Neurochem","first-page":"942","article-title":"Activation by nitric oxide of guanylate cyclase in endothelial cells from brain capillaries.","volume":"59","author":"Marsault","year":"1992"},{"key":"b30","series-title":"J Neurosurg","first-page":"99","article-title":"Production of reactive oxygen species after reperfusion in vitro and in vivo: protective effect of nitric oxide.","volume":"93","author":"Mason","year":"2000"},{"key":"b31","series-title":"Neurosurgery","first-page":"125","article-title":"Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7.","volume":"39","author":"Matsukado","year":"1996"},{"key":"b32","series-title":"Brain Res","first-page":"99","article-title":"Role of nitric oxide in disruption of the blood-brain barrier during acute hypertension.","volume":"686","author":"Mayhan","year":"1995"},{"key":"b33","series-title":"Pharmacol Rev","first-page":"109","article-title":"Nitric oxide: physiology, pathophysiology, and pharmacology.","volume":"43","author":"Moncada","year":"1991"},{"key":"b34","series-title":"Cancer Res","first-page":"4027","article-title":"Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide.","volume":"56","author":"Nakano","year":"1996"},{"key":"b35","series-title":"Brain Res","first-page":"62","article-title":"Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors.","volume":"659","author":"Nomura","year":"1994"},{"key":"b36","series-title":"J Neurosurg","first-page":"746","article-title":"Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage.","volume":"87","author":"Pluta","year":"1997"},{"key":"b37","series-title":"Neurosurgery","first-page":"884","article-title":"Effects of nitric oxide on reactive oxygen species production and infarction size after brain reperfusion injury.","volume":"48","author":"Pluta","year":"2001"},{"key":"b38","series-title":"Am J Clin Oncol","first-page":"609","article-title":"Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial.","volume":"19","author":"Prados","year":"1996"},{"key":"b39","series-title":"J Med Chem","first-page":"4361","article-title":"Localizing antithrombotic and vasodilatory activity with a novel, ultrafast nitric oxide donor.","volume":"39","author":"Saavedra","year":"1996"},{"key":"b40","series-title":"Experientia","first-page":"136","article-title":"Nitric oxide-dependent blood-brain barrier permeability alteration in the rat brain.","volume":"52","author":"Shukla","year":"1996"},{"key":"b41","series-title":"Proc Natl Acad Sci USA","first-page":"7674","article-title":"Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.","volume":"89","author":"Stamler","year":"1992"},{"key":"b42","series-title":"Science","first-page":"1898","article-title":"Biochemistry of nitric oxide and its redox-activated forms.","volume":"258","author":"Stamler","year":"1992"},{"key":"b43","series-title":"Cancer Res","first-page":"914","article-title":"Cyclic GMP-specific phosphodiesterase inhibition and intracarotid bradykinin infusion enhances permeability into brain tumors.","volume":"58","author":"Sugita","year":"1998"},{"key":"b44","series-title":"Neurol Res","first-page":"559","article-title":"Nitric oxide and cyclic GMP attenuate sensitivity of the blood-tumor barrier permeability to bradykinin.","volume":"20","author":"Sugita","year":"1998"},{"key":"b45","series-title":"Neuroreport","first-page":"2577","article-title":"Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma.","volume":"9","author":"Swaroop","year":"1998"},{"key":"b46","series-title":"J Neurooncol","first-page":"69","article-title":"A phase II study of intravenous carboplatin for the treatment of recurrent gliomas.","volume":"19","author":"Warnick","year":"1994"},{"key":"b47","series-title":"Nitric Oxide","first-page":"88","article-title":"Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin.","volume":"1","author":"Wink","year":"1997"},{"key":"b48","series-title":"Carcinogenesis","first-page":"711","article-title":"The multifaceted roles of nitric oxide in cancer.","volume":"19","author":"Wink","year":"1998"},{"key":"b49","series-title":"Cancer Res","first-page":"159","article-title":"Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger.","volume":"58","author":"Wu","year":"1998"}],"container-title":["Journal of Neurosurgery"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/99\/4\/article-p728.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/99\/4\/article-p728.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/99\/4\/article-p728.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:41Z","timestamp":1679270441000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/99\/4\/article-p728.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,10]]},"references-count":49,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.3171\/jns.2003.99.4.0728","relation":{},"ISSN":["0022-3085"],"issn-type":[{"value":"0022-3085","type":"print"}],"subject":[],"published":{"date-parts":[[2003,10]]}}}