Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion

Groothuis, Dennis R.; Ward, Sherman; Itskovich, Andrea C.; Dobrescu, Cosmin; Allen, Cathleen V.; Dills, Cynthia; Levy, Robert M.

doi:10.3171/jns.1999.90.2.0321

Cited by 92 publications

(42 citation statements)

References 22 publications

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“…Firstly, convection-enhanced delivery is a method of local delivery that drives an infusate through the extracellular fluid in neural tissue using a continuous pressure gradient [61]. Experimental studies have shown that convection-enhanced delivery can achieve a local drug concentration 10,000-fold greater than that achieved by intravenous drug administration without causing significant systemic exposure [62, 63]. Secondly, local delivery of chemotherapeutic agents to the brainstem can be achieved via a cannulated screw attached to the skull of the animal [59].…”

Section: Future Directionsmentioning

confidence: 99%

Brainstem Tumors: Where Are We Today?

Recinos

Sciubba

Jallo³

2007

Pediatr Neurosurg

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Brainstem tumors comprise 10–20% of all pediatric central nervous system tumors. The management of these tumors has evolved dramatically in the past century. Once considered uniformly fatal, it is now known that brainstem tumors have distinguishing characteristics and do not behave identically. The focality and location of the lesion is determined from the clinical history, presentation, and associated imaging. Based on these findings, it is possible to predict the behavior of the tumor and choose an appropriate intervention. Focal lesions have a good prognosis and are treated operatively while diffuse lesions have a poor prognosis and are managed medically. This article reviews the current classification of brainstem tumors, current management options and future directions for the treatment of these rare tumors.

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Section: Future Directionsmentioning

confidence: 99%

Brainstem Tumors: Where Are We Today?

Recinos

Sciubba

Jallo³

2007

Pediatr Neurosurg

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“…Unlike intraparenchymal injection, CED does not cause structural or functional damage to the infused tissue, and it provides greater control over the distribution of the therapeutic substance. In CED, solutes are distributed homogeneously throughout a distribution volume that is proportional to the infusion volume regardless of the solute's molecular weight (Bobo et al, 1994;Chen et al, 1999;Groothuis et al, 1999;Occhiogrosso et al, 2003). CED is particularly applicable to slowly diffusing substances of high molecular weight because the distribution of such large solutes is effectively restricted to the region of the infusion.…”

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confidence: 99%

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA

Gąsior

White

Rogawski³

2007

J Pharmacol Exp Ther

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Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists -conotoxin GVIA (-CTX-G) and -conotoxin MVIIA (-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, -CTX-G (0.005, 0.05, and 0.5 nmol), -CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated -CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of -CTX-G and -CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of -conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated -CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders.

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“…49 Investigators compared the concentration of 14 Csucrose in rat brain via intravenous, intrathecal and convectionenhanced delivery and found that convection-enhanced delivery resulted in 10,000-fold increase in tissue concentration of 14 Csucrose versus intravenous delivery. 50 Others have demonstrated that CED of 125 I-boronated epidermal growth factor into rat brains with glioma tumor resulted in 47.4% injected dose/gram (IDg) of the IT being detected within the tumor bed even after 24 hr, whereas intratumoral injection of the IT resulted in only 33% ID/g being detected within the tumor bed 24 hr after injection. 47 To overcome this limitation of DTIL13 in a clinical trial, it is logical that convection-enhanced delivery should be used.…”

Section: Discussionmentioning

confidence: 99%

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

Rustamzadeh

Hall

Todhunter

et al. 2006

Intl Journal of Cancer

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A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model. In vitro studies to determine specificity indicated that the protein called DTIL13 was highly selective for human glioblastoma. In vivo, the maximum tolerated dose of DTIL13 was 1 lg/injection given every other day and repeated for 3 days. Doses that exceeded this amount resulted in weight loss and liver damage as determined by histology and enzyme assay. Experiments in IL-4 receptor knockout mice revealed that liver toxicity was receptorrelated. This same dose given to nude mice with established U373 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging (MRI) proved to be extremely useful in (i) determining the ability of DTIL13 to reduce tumor size and (ii) for studying toxicity since diffusion-weighted and gradient echoweighted MRI revealed that vascular leak syndrome was not a limiting toxicity at this dose. These results suggest that DTIL13 is as effective in an intracranial rodent model as it was in a flank model in previous studies and that DTIL13 might be an effective treatment for glioblastoma multiforme. ' 2005 Wiley-Liss, Inc.Key words: diphtheria toxin; glioblastoma; interleukin-13; brain tumor; immunotoxin Glioblastoma multiforme (GBM) is an incurable, heterogeneous, high-grade astrocytic glioma, thought to originate from glial nonneuronal cells. 1 More recent studies have identified a subpopulation of cancer stem-cells within GBM that retain the capacity for self-renewal and the ability to differentiate into a phenotypically diverse population of cells. 2-4 With a 2-year-patient survival rate of <30%, 5 effective treatment has been hindered by the lack of tumor-specific markers in the majority of patients. Recently, the IL-13 receptor (IL-13R) has been found to be overexpressed on cultured human GBM cell lines and surgical GBM specimens, but is not detectable in normal brain tissue. [6][7][8] Targeting the IL-13 receptor with an immunotoxin (IT) has already proven to have potential for treating brain tumors. [8][9][10][11][12] ITs are not mainstream pharmaceuticals, and treatment of systemic tumors with ITs has been limited by their failure to localize in tumor. The promise of these drugs is considerably greater for brain-cancer therapy, since IT can be directly administered intracranially. In an earlier study, we assembled an IL-13 IT made by fusing gene fragments encoding for human IL-13 and the first 389 amino acids of diphtheria toxin. 13 In vivo studies with this agent showed that it had a potent antitumor effect against IL-13R-positive GBM cells grown in the flanks of nude mice without significant toxicity.Although encouraging, the flank model has limitations as a model for intracranial therapy. First, intratumoral pressure within the flank model does not reach the pressures that occur in intracranial tumors ...

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Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion

Abstract: Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.

Cited by 92 publications

References 22 publications

Brainstem Tumors: Where Are We Today?

Brainstem Tumors: Where Are We Today?

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

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