Uptake of tritiated methotrexate by mouse brain tumors after intravenous or intrathecal administration

1974 ◽  
Vol 40 (6) ◽  
pp. 706-716 ◽  
Author(s):  
Yukitaka Ushio ◽  
Toru Hayakawa ◽  
Heitaro Mogami
Keyword(s):  
Brain Tumors ◽  
Brain Tissue ◽  
Intravenous Injection ◽  
Malignant Gliomas ◽  
Intrathecal Administration ◽  
Drug Dosage ◽  
Content Type ◽  
Radioactive Assay ◽  
The Brain ◽  
Fine Print

✓ Malignant gliomas were induced in strain ddN mice by intracerebral implantation of a 20-methylcholanthrene pellet. The uptake and distribution of tritiated methotrexate (MTX-3H) in the tumor were investigated by radioactive assay and radioautography after single intravenous or intrathecal injections. By either route, a large amount of MTX-3H was taken up by gliomas, and a significantly higher concentration was observed in tumor than in the brain tissue. At 24 hours after intrathecal administration, the uptake of MTX-3H by gliomas exceeded that achieved after intravenous injection, although the drug dosage in the latter was 10 times that in the former.

Thymidine kinase-mediated killing of rat brain tumors

1993 ◽  
Vol 79 (5) ◽  
pp. 729-735 ◽  
Author(s):  
David Barba ◽  
Joseph Hardin ◽  
Jasodhara Ray ◽  
Fred H. Gage
Keyword(s):  
Gene Therapy ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Wild Type ◽  
Cns Disorders ◽  
Content Type ◽  
Potential Applications ◽  
Ganciclovir Treatment ◽  
The Brain ◽  
Fine Print

✓ Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 µg ganciclovir/ml; C6, 5.0 µg ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.

Site-specific immune response to implanted gliomas

2001 ◽  
Vol 95 (6) ◽  
pp. 1012-1019 ◽  
Author(s):  
Martin A. Proescholdt ◽  
Marsha J. Merrill ◽  
Barbara Ikejiri ◽  
Stuart Walbridge ◽  
Aytac Akbasak ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Growth ◽  
Mhc Class Ii ◽  
Lymphocytic Infiltration ◽  
Class Ii ◽  
Content Type ◽  
Time Points ◽  
Early Tumor ◽  
The Brain ◽  
Fine Print

Object. Immunotherapy for glioblastoma has been uniformly ineffective. The immunological environment of the brain, with its low expression of major histocompatibility complex (MHC) molecules and limited access for inflammatory cells and humoral immune effectors due to the blood—brain barrier (BBB), may contribute to the failure of immunotherapy. The authors hypothesize that brain tumors are protected from immune surveillance by an intact BBB at early stages of development. To investigate the immunological characteristics of early tumor growth, the authors compared the host response to a glioma implanted into the brain and into subcutaneous tissue. Methods. Samples of tumors growing in the brain or subcutaneously in rats were obtained for 7 consecutive days and were examined immunohistochemically for MHC Class I & II molecules, and for CD4 and CD8 lymphocyte markers. Additionally, B7-1 costimulatory molecule expression and lymphocyte-specific apoptosis were examined. Conclusions. On Days 3 and 4 after implantation, brain tumors displayed significantly lower MHC Class II expression and lymphocytic infiltration (p < 0.05). After Day 5, however, no differences were detected. The MHC Class II expressing cells within the brain tumors appeared to be infiltrating microglia. Minimal B7-1 expression combined with lymphocyte-specific apoptosis were detected in both brain and subcutaneous tumors. Low MHC Class II expression and low lymphocytic infiltration at early time points indicate the importance of the immunologically privileged status of the brain during early tumor growth. These characteristics disappeared at later time points, possibly because the increasing perturbation of the BBB alters the specific immunological environment of the brain. The lack of B7-1 expression combined with lymphocyte apoptosis indicates clonal anergy of glioma-infiltrating lymphocytes regardless of implantation site.

Chemotherapy for malignant gliomas

1988 ◽  
Vol 68 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Paul L. Kornblith ◽  
Michael Walker
Keyword(s):  
Clinical Management ◽  
Malignant Gliomas ◽  
New Agents ◽  
Specific Patient ◽  
Content Type ◽  
Number Of Patients ◽  
New Findings ◽  
The Impact ◽  
The Brain ◽  
Fine Print

✓ There continues to be an extensive effort to develop chemotherapeutic approaches to the treatment of malignant gliomas of the brain. In the past 5 years there have been literally hundreds of trials of new agents, combinations of old and new agents, and even new routes and approaches to the delivery of chemotherapy. In this review, the literature has been studied and the individual reports analyzed to evaluate the impact of the new findings on clinical management of the patient with malignant glioma of the brain. The major areas of progress include the addition of new drugs with varying modes of action, the use of combinations of drugs in a synergistic fashion, and the development of new routes of drug delivery. None of the advances has brought about the revolution in clinical care that is so eagerly sought, but clearly the amount of new knowledge gained by these studies helps in understanding how to use chemotherapy more effectively. Furthermore, the remarkable degree of interest and involvement in the use of chemotherapy promises that an even greater number of patients with malignant gliomas will be considered for vigorous and enthusiastic clinical management programs even if chemotherapy itself is not the key modality in the treatment of a specific patient.

Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes

1992 ◽  
Vol 76 (3) ◽  
pp. 513-519 ◽  
Author(s):  
Stephen C. Saris ◽  
Paul Spiess ◽  
Daniel M. Lieberman ◽  
Shan Lin ◽  
Stuart Walbridge ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Similar Response ◽  
Content Type ◽  
Primary Brain Tumors ◽  
Infiltrating Lymphocytes ◽  
The Brain ◽  
Fine Print

✓ Methods have recently been described for the isolation and expansion of lymphocytes that have trafficked into animal and human tumors. These CD8-positive tumor-infiltrating lymphocytes (TIL's) have exceptional trafficking ability to, and efficacy against, tumor targets in extracranial sites. Prior to Phase I clinical trials for patients with gliomas, adoptive immunotherapy with TIL's was studied in a mouse model of primary brain tumors to determine if intracerebral tumors have a similar response. Glioma 261 (GL261) tumors were grown in the subcutaneous space of C57BL/6 mice. After enzymatic digestion, the cells were incubated in vitro with interleukin-2 (IL-2) until a confluent population of T lymphocytes was present. The in vitro efficacy of these TIL's was tested against fresh GL261 targets with a chromium release assay; the in vivo efficacy was tested against GL261 tumors in the liver and against irradiated and nonirradiated GL261 tumors in the brain. Mice received one of the following: intraperitoneal saline; intraperitoneal IL-2 (7500 to 50,000 U three times daily for 5 days); IL-2 plus intravenous TIL's (1 to 3 × 107 cells); 10 Gy cranial irradiation; irradiation plus IL-2; or irradiation plus IL-2 plus TIL's. The TIL preparation killed 77% of tumor targets in 4 hours at an effector:target ratio of 100:1. In animals with GL261 tumors in the liver, at 2 weeks there were 93 ± 37, 128 ± 45, and 21 ± 14 liver metastases in the control, IL-2, and IL-2 plus TIL groups, respectively. However, in animals with GL261 tumors in the brain, no treatment group had an increased survival rate compared to the control group. It is concluded that, although TIL and IL-2 immunotherapy can be used effectively to treat brain tumors in vitro and at sites outside the central nervous system, it is ineffective against the same type of tumor in the brain. Different methods of delivery or different combinations of these immunomodulators may be more effective; however, based on these findings, treatment of patients with IL-2 and TIL cannot be recommended until efficacy has been demonstrated in an animal model.

Influence of oxygen therapy on glucose—lactate metabolism after diffuse brain injury

2004 ◽  
Vol 101 (2) ◽  
pp. 323-329 ◽  
Author(s):  
Michael Reinert ◽  
Benoit Schaller ◽  
Hans Rudolf Widmer ◽  
Rolf Seiler ◽  
Ross Bullock
Keyword(s):  
Brain Injury ◽  
Brain Tissue ◽  
Brain Metabolism ◽  
Arterial Line ◽  
Content Type ◽  
Diffuse Brain Injury ◽  
Lactate Levels ◽  
The Brain ◽  
Fine Print ◽  
Diffuse Brain

Object. Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. Methods. A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. Conclusions. Increasing the FiO2 influences dialysate glucose and lactate levels in injured brain tissue. Using an FiO2 of 1 influences brain metabolism in such a way that lactate is significantly reduced and glucose significantly increased. No changes in dialysate glucose and lactate values were found in the noninjured brain.

Progressive ventricular enlargement in cats in the absence of transmantle pressure gradients

1987 ◽  
Vol 67 (1) ◽  
pp. 88-92 ◽  
Author(s):  
Kenneth Shapiro ◽  
Ira J. Kohn ◽  
Futoshi Takei ◽  
Corinna Zee
Keyword(s):  
Brain Tissue ◽  
Subarachnoid Space ◽  
Pressure Gradients ◽  
Content Type ◽  
Cisterna Magna ◽  
Sagittal Sinus ◽  
Intracisternal Injection ◽  
The Mean ◽  
The Brain ◽  
Fine Print

✓ Intracranial pressure (ICP) was measured simultaneously at multiple sites in cats to determine if transmantle pressure gradients were present in progressive hydrocephalus. The cats underwent craniectomy and intracisternal injection of kaolin; 4 to 9 weeks later ICP was measured at the ventricle, cisterna magna, and convexity subarachnoid space, and in the brain tissue and the sagittal sinus. In 13 cats in which ventricular size conformed to previously established norms for duration of hydrocephalus, there were no demonstrable gradients of pressure at any of the sites of measurement according to one-way analysis of variance (p > 0.05). The mean (± standard error of the mean) peak and trough pressures (in mm Hg) at each site were: ventricle, 12.7 ± 0.7 and 12.0 ± 0.6; cisterna magna, 12.9 ± 0.8 and 12.3 ± 0.7; subarachnoid space, 12.7 ± 0.8 and 12.1 ± 0.7; brain tissue, 12.9 ± 0.9 and 12.4 ± 0.9; and sagittal sinus, 13.1 ± 0.8 and 11.9 ± 0.8. These results indicate that ventricular expansion can progress without measurable transmantle pressure gradients.

Carbohydrates as potential diagnostic tracers for brain tumors

1976 ◽  
Vol 44 (6) ◽  
pp. 668-675 ◽  
Author(s):  
Willem Wassenaar ◽  
Charles H. Tator
Keyword(s):  
Brain Tumors ◽  
Intravenous Injection ◽  
Tumor Metabolism ◽  
Scintillation Counting ◽  
Axial Tomography ◽  
Content Type ◽  
Transplantable Mouse ◽  
Specific Tumor ◽  
Computerized Axial Tomography ◽  
Fine Print

✓ Currently available diagnostic tracers for brain tumors are not specific. Tumor-specific tracers would improve the detection of brain tumors by gamma encephalography. Glucose is an important substrate for tumor metabolism and is known to be taken up in large amounts. The authors have studied five labeled carbohydrates in an attempt to find a tumor-specific tracer: three were tritiated (L-galactose-1-3H, L-fucose-3H, and 4,6-dideoxy-xylo-hexose-3H) and two were radioiodinated (methyl-6-125I-6-deoxy-D-glucoside and 6-125I-6-deoxy-D-glucose). The uptake of these tracers by a transplantable mouse ependymoblastoma after intravenous injection was determined by liquid and well scintillation counting. The highest tumor-to-brain ratio was 7.1 to 1 for the tritiated tracers and 6.2 to 1 for the radioiodinated tracers. Although these ratios are not high enough for gamma encephalography, one of the iodinated tracers may be useful for enhancement of contrast in computerized axial tomography.

Acetazolamide therapy for symptomatic plateau waves in patients with brain tumors

2002 ◽  
Vol 97 (1) ◽  
pp. 224-226 ◽  
Author(s):  
Christopher J. Watling ◽  
J. Gregory Cairncross
Keyword(s):  
Intracranial Pressure ◽  
Carbonic Anhydrase ◽  
Brain Tumors ◽  
Neurological Disorder ◽  
Malignant Gliomas ◽  
Effective Therapy ◽  
Content Type ◽  
Plateau Waves ◽  
Dexamethasone Therapy ◽  
Fine Print

✓ In this report, the authors describe three patients with malignant gliomas who experienced paroxysmal neurological symptoms triggered by standing. The symptoms were attributed to acute elevations of intracranial pressure, an uncommon phenomenon called “plateau waves.” In each instance, the attacks occurred despite the fact that the patient was receiving dexamethasone therapy and stopped promptly with the addition of acetazolamide. Acetazolamide, an orally administered carbonic anhydrase inhibitor, appears to be a specific and effective therapy for this uncommon neurological disorder.

Brain-tumor imaging using radiopaque perfluorocarbon

1983 ◽  
Vol 58 (5) ◽  
pp. 650-653 ◽  
Author(s):  
Nicholas J. Patronas ◽  
Javad Hekmatpanah ◽  
Kunio Doi
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Contrast Agent ◽  
Contrast Medium ◽  
Computerized Tomography ◽  
Tumor Imaging ◽  
Content Type ◽  
X Ray ◽  
The Brain ◽  
Fine Print

✓ Perfluorocarbon, a new tumor-seeking x-ray contrast agent, was injected into three rats with experimental brain tumors. After 1 to 3 days the rats were sacrificed, and the brains were removed and subjected to x-ray study. All showed dense radiopaque areas which correlated with the size and shape of the corresponding brain tumors. Conversely, none of the radiograms taken of the brain tumor in five rats receiving no perfluorocarbon (control animals) showed similar increased density. These findings suggest that perfluorocarbon may serve a useful role as a contrast medium for computerized tomography studies of brain tumors in man.

The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

1992 ◽  
Vol 76 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Stuart A. Grossman ◽  
Carla Reinhard ◽  
O. Michael Colvin ◽  
Mark Chasin ◽  
Robert Brundrett ◽  
...  
Keyword(s):  
New Zealand ◽  
Brain Tissue ◽  
Direct Injection ◽  
Normal Brain ◽  
Local Concentration ◽  
Content Type ◽  
Drug Concentrations ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

Sign in / Sign up

Export Citation Format

Share Document