Theoretical Considerations in the Chemotherapy of Brain Tumors

Cowles, Alan L.; Fenstermacher, Joseph D.

doi:10.1007/978-3-642-65678-1_16

Cited by 6 publications

(8 citation statements)

References 20 publications

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“…The principle advantage of this method is that during the course of injecting a drug into an artery, the tissue perfused by that artery receives a higher plasma concentration during the first passage through the circulation (AUC PL is increased). In a series of papers, Fenstermacher and coworkers theoretically evaluated the efficacy of intra-arterial delivery to the brain and brain tumors (Cowles and Fenstermacher, 1974;Eckman et al, 1974;Fenstermacher and Cowles, 1977;Fenstermacher and Gazendam, 1981). They evaluated the contributions of several variables and concluded that there were significant delivery advantages to i.a.…”

Section: Intra-arterial Administrationmentioning

confidence: 99%

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Groothuis¹

2000

Neuro-Oncol

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Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intraarterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug ef ux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal uid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors. Neuro-Oncology 2, 45-59, 2000 (Posted to Neuro-Oncology [serial online], Doc. 99-30, December 14, 1999 IntroductionThe delivery of drugs to brain tumors has long been a controversial problem. In 1977, Vick et al. wrote in an editorial: "We believe that there is compelling evidence to suggest that the 'blood-brain barrier,' as it is generally conceived, is not one of the factors impeding the success of brain tumor chemotherapy." They went on to say that "dosage, route of administration, tumor cell uptake, metabolic fate within tumor cells, and the washout or sink effect of the extracellular space and CSF are the issues that will have to be studied" (Vick et al., 1977). Some clinicians have agreed with Vick et al. (Donelli et al., 1992;Stewart, 1994); however, on the whole, the belief that the BBB 3 and BTB prevent drugs from reaching brain tumors in suf cient concentrations to kill the tumor cells has motivated numerous attempts to increase the amount of drug that reaches the tumor. Many innovative methods have been used to try to increase drug delivery including, most recently, a method in which drugs are infused directly into brain tumors, a method referred to as convection-enhanced delivery (CED) Laske et al., 1997a;Lieberman et al., 1995). This review Neuro-Oncology n J AN UA RY 2 0 00 45Neuro-Oncology

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Section: Intra-arterial Administrationmentioning

confidence: 99%

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Groothuis¹

2000

Neuro-Oncol

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“…Using both the carotid flow rates and Clsy s values obtained above, a theoretical R d for these rabbits with BCNU IA infusions was calculated using the following equation [1][2][3]:…”

Section: Theoretical Modeling Predictionsmentioning

confidence: 99%

“…Equations developed to predict the advantage of IA infusions apply only to total drug exposure of the target tissue [1][2][3].…”

Section: Modelingmentioning

confidence: 99%

“…Modeling equations have been developed to predict the total drug exposure to the target tissue with IA delivery as compared to intravenous (IV) delivery [1][2][3]. The modeling predicts higher concentrations of drug in the blood supplying the tumor and an increased concentration gradient of the drug from the vascular space to the tumor tissue compartment [3].…”

Section: Introductionmentioning

confidence: 99%

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Predicted and actual BCNU concentrations in normal rabbit brain during intraarterial and intravenous infusions

1996

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Normal New Zealand White rabbits were used to compare theoretical brain concentrations (based upon pharmacokinetic modeling) with actual experimental concentrations of BCNU following intraarterial (IA) or intravenous (IV) infusions. IA infusion therapy for brain tumor patients has been promising based upon theoretical predictions but of limited effectiveness clinically. Experimentally-measured rabbit carotid artery flow rates (63.9 +/- 3.4 ml/min) [mean +/- 1 sem] and BCNU systemic clearances (197 +/- 10.2 ml/min) predicted a theoretical IA advantage of 4.1 +/- 0.2. Ipsilateral brain concentrations of BCNU during and after IA infusions (20 mg/min/m2 over 15 minutes) were: 16.2 +/- 2.9, 19.0 +/- 3.9, 20.3 +/- 2.8, 4.8 +/- 2.5, 2.1 +/- 1.5, and 1.7 +/- 1.6 micrograms/gm brain at 5, 10, 15, 25, 35, and 45 minutes after infusion start. Mean concentrations at same time points in contralateral hemisphere (IA infusions) were: 7.1 +/- 1.8, 9.0 +/- 1.8, 10.3 +/- 0.7, 4.2 +/- 1.4, 2.2 +/- 1.2, 2.0 +/- 1.5 micrograms/gm brain. Concentrations in either hemisphere during IV infusions were similar to contralateral hemisphere during IA infusions. Comparison of ipsilateral: contralateral hemisphere ratios during and after IA infusions were: 3.2 +/- 0.4, 2.6 +/- 0.3, 2.2 +/- 0.3, 1.1 +/- 0.3, 1.0 +/- 0.4, and 0.9 +/- 0.3 at the same time points. Although these data show higher drug concentrations with IA infusions, actual values were considerably less than predicted by theoretical modeling. This discrepancy between theoretical and experimental results emphasizes need for further study of causes and remedies so that IA therapy can achieve better drug concentrations with less toxicity.

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“…Hier hat jedes Medikament seine eigene Charakteristik. 4. Durch die regionäre Konzentrationssteigerung der Wirksubstanz (en) könnte nicht nur eine Steigerung der ,,zytostatischen" Wirkung sondern eine (nicht-lineare) ,,tumortoxische" Wirkung erzielt werden.…”

unclassified

Erste klinische Erfahrungen mit einer neuen Methode intraarterieller Chemotherapie maligner Tumoren im Kopf-Hals-Bereich*

Scheel¹,

Kastenbauer²

1982

Laryngo-Rhino-Otol

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Theoretical Considerations in the Chemotherapy of Brain Tumors

Cited by 6 publications

References 20 publications

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Predicted and actual BCNU concentrations in normal rabbit brain during intraarterial and intravenous infusions

Erste klinische Erfahrungen mit einer neuen Methode intraarterieller Chemotherapie maligner Tumoren im Kopf-Hals-Bereich*

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