Tumor-associated neurological dysfunction prevented by lazaroids in rats

1991 ◽  
Vol 74 (1) ◽  
pp. 112-115 ◽  
Author(s):  
Wesley A. King ◽  
Keith L. Black ◽  
Kiyonobu Ikezaki ◽  
Scott Conklin ◽  
Donald P. Becker
Keyword(s):  
Vascular Permeability ◽  
Tumor Model ◽  
Neurological Dysfunction ◽  
Control Group ◽  
Content Type ◽  
Brain Tumor Model ◽  
Walker 256 ◽  
Walker 256 Tumors ◽  
Fine Print ◽  
Better Than

✓ The efficacy of U-74006F and U-78517F in the treatment of blood-tumor barrier permeability and tumor-associated neurological dysfunction was evaluated in a brain-tumor model in rats. U-74006F is a 21-aminosteroid and U-78517F is a 2-methylamino chroman. Rats with stereotactically implanted Walker 256 tumors were treated with methylprednisolone, U-74006F, U-78517F, or vehicle (0.05 N HCl) on Days 6 through 10 following implantation. Neurological function and vascular permeability were assessed on Day 10. Methylprednisolone and U-74006F were equally effective at preventing neurological dysfunction compared to the control group (p < 0.01); U-78517F was slightly less effective than U-74006F and methylprednisolone but was significantly better than vehicle in preventing neurological dysfunction. Delivery of methylprednisolone resulted in a significant decrease in tumor vascular permeability (p < 0.006) while U-74006F and U-78517F had no effect on permeability. This suggests that U-74006F and U-78517F prevented tumor-associated neurological dysfunction by a mechanism other than decreasing permeability in tumor capillaries, and that U-74006F or U-78517F could prove useful in the treatment of brain tumors.

Improved treatment of a brain-tumor model

1983 ◽  
Vol 58 (2) ◽  
pp. 177-182 ◽  
Author(s):  
Mark L. Rosenblum ◽  
Massimo A. Gerosa ◽  
Dolores V. Dougherty ◽  
Charles B. Wilson
Keyword(s):  
Brain Tumor ◽  
Tumor Model ◽  
Clinical Effects ◽  
Content Type ◽  
Animal Survival ◽  
Fractionation Schedule ◽  
Brain Tumor Model ◽  
Clonogenic Cell ◽  
Survival Studies ◽  
Fine Print

✓ Clonogenic cell and animal survival studies were used to determine the most effective BCNU therapy schedule in the 9L rat brain-tumor model. Survival of tumor cells following a single LD10 dose of BCNU (13.3 mg/kg intraperitoneally) was compared to cell survival after one to four daily 0.5 × LD10 doses. The posttreatment kinetics of surviving clonogenic cells were investigated at various times after BCNU was given in single doses of 0.25 to 1 × LD10 and in two daily doses of 0.5 × LD10. The cell kill was greater, time to reinitiation of cell growth was later, posttreatment rate of clonogenic cell proliferation was slower, and the interval to total repopulation of the clonogenic cell pool was longer with a single LD10 dose as compared to the multiple-dose schedules. Animal survival studies confirmed that a single LD10 dose of BCNU was at least as effective as a cumulative level of up to 1½ times that amount when treatment was administered in smaller doses, regardless of the fractionation schedule. Clinical experience with patients harboring malignant brain tumors has shown that a single BCNU dose of 185 to 200 mg/sq m is tolerated well. Results of these animal experiments suggest that this therapy should have anti-tumor activity at least equivalent to the more commonly employed schedule of 80 mg/sq m/day given for 3 days. Although direct comparison of treatment efficacy using the two schedules is not possible, no adverse clinical effects have been observed with the recently adopted single-dose schedule. Furthermore, the duration of patient hospitalization for chemotherapy has decreased.

A controlled study of efficacy of interstitial or external irradiation in a virus-induced brain-tumor model in rats

1989 ◽  
Vol 71 (6) ◽  
pp. 898-902 ◽  
Author(s):  
Yehia El-Hennawi ◽  
G. Yancey Gillespie ◽  
M. Stephen Mahaley ◽  
Mahesh A. Varia ◽  
Darell D. Bigner ◽  
...  
Keyword(s):  
Tumor Model ◽  
Controlled Study ◽  
External Irradiation ◽  
Virus Inoculation ◽  
Content Type ◽  
Interstitial Radiotherapy ◽  
Sarcoma Virus ◽  
Brain Tumor Model ◽  
Avian Sarcoma ◽  
Fine Print

✓ In a controlled study of interstitial radiotherapy in the avian sarcoma virus (ASV)-induced glioma model in rats, prolongation of survival was demonstrated (p = 0.08 in Experiment 1 and p = 0.03 in Experiment 2) following mean dosages of 7582 to 9902 cGy 125I, when compared to nontreatment or to control studies with implantation of nonradioactive seeds. More significant (p = 0.02) prolongation of survival was demonstrated following external beam whole-head radiotherapy with nine fractions of 333 cGy, three times weekly over 3 weeks (total dose 3000 cGy). Survival was more prolonged when whole-head radiotherapy was begun 35 days following virus inoculation rather than at 71 days, probably reflecting a greater efficacy with smaller tumor targets.

The effect of amphotericin B on the survival of brain-tumor-bearing mice treated with CCNU

1978 ◽  
Vol 49 (4) ◽  
pp. 579-588 ◽  
Author(s):  
Paul J. Muller ◽  
Charles H. Tator
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Amphotericin B ◽  
Intraperitoneal Administration ◽  
Tumor Model ◽  
Chemotherapeutic Agents ◽  
Control Group ◽  
Content Type ◽  
Tumor Bearing ◽  
Fine Print

✓ The membrane-active polyene, amphotericin B (AMB) has been shown to enhance or potentiate the effects of various chemotherapeutic agents against tumor cells in tissue culture. Because of the need to increase the efficacy of the nitrosoureas in brain-tumor chemotherapy, we have studied the effect of the nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), with or without AMB pretreatment. The intraperitoneal administration of 25 mg/kg of AMB 24 hours before 5, 10, 20, or 30 mg/kg of intraperitoneal CCNU did not result in a significant improvement in survival. The failure of intraperitoneal AMB to potentiate the effect of CCNU was likely a failure in drug delivery, since AMB crosses the blood-brain barrier very poorly. To circumvent the drug-delivery problem, AMB was administered intracerebrally directly into the tumor-bearing hemisphere. With 0.5 mg/kg of intracerebral AMB administered 24 hours before 10 mg/kg CCNU was given intraperitoneally, the life-span was significantly increased over the control group. The same dose of CCNU alone did not significantly increase survival. When 0.2, 0.5, or 1.0 mg/kg AMB was administered intracerebrally 24 hours before 20 mg/kg of intraperitoneal CCNU, survival was significantly increased over those groups receiving the same dose of CCNU alone. It is concluded that direct intracerebral administration of AMB enhances or potentiates the therapeutic effect of CCNU in this brain-tumor model.

Invasive phenotype observed in 1,3-bis(2-chloroethyl)-1-nitrosourea—resistant sublines of 9L rat glioma cells: a tumor model mimicking a recurrent malignant glioma

2004 ◽  
Vol 101 (5) ◽  
pp. 826-831 ◽  
Author(s):  
Ryuta Saito ◽  
John Bringas ◽  
Hanna Mirek ◽  
Mitchel S. Berger ◽  
Krys S. Bankiewicz
Keyword(s):  
Drug Resistance ◽  
Tumor Model ◽  
Growth Patterns ◽  
Invasive Growth ◽  
Content Type ◽  
Rat Glioma ◽  
Brain Tumor Model ◽  
Fine Print

Object. Chemotherapy is suspected of having an effect on the generation of phenotypical heterogeneity and the development of drug resistance in tumors. Recurrent gliomas feature drug resistance as well as greater invasive growth than original tumors. The authors investigated phenotypical changes in invasion observed in 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)—resistant sublines of the 9L rat gliosarcoma. Methods. Two established BCNU-resistant sublines, derived from 9L gliosarcoma cells by treating these cells with BCNU in vivo or in vitro, were used in the study. An in vitro examination confirmed the resistance of the cells to BCNU treatment. The cells were implanted into the striatum of Fisher 344 rats, and histological examinations were performed to compare the growth patterns of the resultant tumors. A new brain tumor model was established by implanting 9L-2 cells in Fisher 344 rats. The 9L-2 and BTRC-19 cells displayed a distinct increase in BCNU resistance compared with the 9L cells. Both BCNU-resistant sublines developed a tumor mass with invasive margins, which is not the case with 9L tumor models. The newly developed 9L-2 tumor model demonstrated 100% tumor uptake with consistent growth patterns. Conclusions. Cells that acquire drug resistance also demonstrated invasive growth. Because the 9L-2 and BTRC-19 cells were derived from 9L cells that had been treated with BCNU in vivo and in vitro, this change in phenotype was likely caused by the drug treatment, which may have implications for chemotherapy of gliomas. The tumor model that developed from the 9L-2 cells can be used as a model of a recurrent glioma, which features drug resistance and invasive growth.

An improved rat brain-tumor model

1980 ◽  
Vol 53 (6) ◽  
pp. 808-815 ◽  
Author(s):  
Naoki Kobayashi ◽  
Norman Allen ◽  
Nancy R. Clendenon ◽  
Li-Wen Ko
Keyword(s):  
Rat Brain ◽  
Tumor Model ◽  
Injection Technique ◽  
Tumor Implantation ◽  
Content Type ◽  
Rat Brain Tumor ◽  
Brain Tumor Model ◽  
System Tumor ◽  
Intracerebral Tumor ◽  
Fine Print

✓ The widely used intracerebral tumor implantation method by freehand injection into parietal or hippocampal areas of the rat brain has proven inadequate for reliable experimental therapeutic studies. Problems include poor intracerebral growth yields and significant rates of spread to extracranial tissues, lungs, and spinal cord. Major variables have been examined experimentally on a model using nitrosourea-induced nervous system tumor cell lines in syngeneic rats. A rapid stereotaxic method greatly improved the consistency of tumor placement. The optimal site was found to be the caudate nucleus. The production of a spheroid intracerebral growth was further facilitated by the use of 1% agar in the cell suspension medium and by an injection volume of 10 µl containing at least 104 cells. Further improvements involved injection technique and flushing of the operative field. These modifications have resulted in a 99% to 100% yield of intracerebral growth, with a marked reduction in the number and size of extracranial extensions and with distant metastasis rates of 0% to 5%. These results have continually improved with further experience. The method is satisfactory for radiation and chemotherapeutic trials in which survival time as an index of tumor size may be used as an end point.

Distribution of hematoporphyrin derivative in the rat 9L gliosarcoma brain tumor analyzed by digital video fluorescence microscopy

1984 ◽  
Vol 61 (6) ◽  
pp. 1113-1119 ◽  
Author(s):  
James E. Boggan ◽  
Robert Walter ◽  
Michael S. B. Edwards ◽  
Janis K. Borcich ◽  
Richard L. Davis ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Model ◽  
Normal Brain ◽  
Hematoporphyrin Derivative ◽  
Content Type ◽  
9L Gliosarcoma ◽  
Video Fluorescence Microscopy ◽  
Brain Tumor Model ◽  
The Brain ◽  
Fine Print

✓ A digital video fluorescence microscopy technique was used to evaluate the distribution of hematoporphyrin derivative (HPD) in the rat intracerebral 9L gliosarcoma brain-tumor model at 4, 24, 48, and 72 hours after intravenous administration of 10 mg/kg of the drug. Compared to surrounding normal brain, there was significant preferential uptake of HPD into the tumor. In sections surveyed, fluorescence reached a maximum value by 24 hours; however, only 33% to 44% of the tumor was fluorescent. In contrast, fluorescence within the surrounding normal brain was maximum at 4 hours, but was present in less than 1% of the brain tissue evaluated. The effect of HPD sensitization to a laser light dose (633 nm) of 30 joules/sq cm delivered through the intact skull was evaluated histologically in 10 rats. A patchy coagulation necrosis, possibly corresponding to the distribution of HPD fluorescence seen within the tumor, was observed. There was evidence that photoradiation therapy (PRT) affects defective tumor vasculature and that a direct tumor cell toxicity spared normal brain tissue. Despite these findings, limited uptake of HPD in tumor and the brain adjacent to tumor may decrease the effectiveness of PRT in the 9L gliosarcoma brain-tumor model. Because of the similarity between the capillary system of the 9L tumor and human brain tumors, PRT may have a limited therapeutic effect in patients with malignant brain tumors.

The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain tumor model

1980 ◽  
Vol 52 (3) ◽  
pp. 359-366 ◽  
Author(s):  
Paul J. Muller ◽  
Charles H. Tator ◽  
Martin Bloom
Keyword(s):  
Brain Tumors ◽  
Tumor Model ◽  
Microsomal Enzymes ◽  
Tumoricidal Activity ◽  
Potent Inducer ◽  
Content Type ◽  
Brain Tumor Model ◽  
High Doses ◽  
Hepatic Microsomal Enzymes ◽  
Fine Print

✓ The nitrosoureas are known to be substrates for hepatic microsomal enzymes. Since phenobarbital (PB) is a potent inducer of hepatic microsomal enzymes, and since PB and other enzyme-inducing drugs are commonly used in patients with brain tumors, the authors have assessed the effect of PB pretreatment on the toxic and tumoricidal activity of CCNU in a murine model. In C57B1/6J mice, PB pretreatment markedly reduced the lethal toxicity of high doses of CCNU. The LD99 dose of CCNU was found to be 80 mg/kg given intraperitoneally. Pretreatment with PB reduced the toxic death rate of CCNU at 40, 60, 90, or 120 mg/kg to less than 10% (p < 0.01). Pretreatment with PB also reduced the tumoricidal activity of CCNU. In an intracerebral murine ependymoblastoma, intraperitoneal CCNU alone, at 30 mg/kg given on the 5th day after tumor transplantation, produced a percent increased life span (%ILS) of > 300, and 18 of 25 were long-term survivors (LTS). In contrast, after four daily doses of PB prior to the same dose of CCNU, the %ILS was reduced to 85 with no LTS among 25 mice (p < 0.01). When CCNU was given alone at 30 mg/kg intraperitoneally on Day 10, a %ILS of > 300 with 22 of 25 LTS resulted; whereas, PB pretreatment reduced the %ILS to 15, with two of 25 LTS (p < 0.01). When CCNU was administered directly into the tumors intracerebrally at 30 mg/kg on Day 10, the %ILS was > 300, with 16 of 20 LTS; whereas, PB pretreatment reduced the %ILS to 50 with five of 20 LTS (p < 0.01). Furthermore, PB pretreatment significantly reduced the ability of CCNU to retard tumor growth in a subcutaneous murine ependymoblastoma. Thus, PB pretreatment significantly altered the activity of CCNU. Since enzyme-inducing drugs are so commonly used in patients with brain tumors, it is possible that the clinical failure of nitrosoureas in some cases may be due to an unsuspected drug antagonism.

The development of an intracerebral glioma model for brain tumor chemotherapy

1973 ◽  
Vol 39 (3) ◽  
pp. 293-301 ◽  
Author(s):  
Willem Wassenaar ◽  
Charles H. Tator ◽  
Wei Sum So
Keyword(s):  
Brain Tumor ◽  
Low Cost ◽  
Tumor Model ◽  
Survival Curves ◽  
Content Type ◽  
Brain Tumor Model ◽  
The Right ◽  
Short Time ◽  
Brain Tumor Chemotherapy ◽  
Fine Print

✓ The authors describe a brain tumor model for chemotherapy studies. The tumor is an intracerebral ependymoblastoma that kills the host in a short time (median survival, 27.5 days) and yields consistent, uniform survival curves. A suspension of tumor cells is injected into the right frontal lobe of the mouse by means of a stereotaxic frame, and produces a highly invasive, almost entirely intracranial brain tumor. The use of mice permits extensive chemotherapeutic trials for brain tumors at low cost. It is felt that this model will prove to be very useful for studies of brain tumor chemotherapy.

Evaluation of endorphin content in the CSF of patients with trigeminal neuralgia before and after Gasserian ganglion thermocoagulation

1981 ◽  
Vol 55 (6) ◽  
pp. 935-937 ◽  
Author(s):  
Giuseppe Salar ◽  
Salvatore Mingrino ◽  
Marco Trabucchi ◽  
Angelo Bosio ◽  
Carlo Semenza
Keyword(s):  
Cerebrospinal Fluid ◽  
Trigeminal Neuralgia ◽  
Control Group ◽  
Gasserian Ganglion ◽  
Content Type ◽  
Group Of Seven ◽  
Idiopathic Trigeminal Neuralgia ◽  
Significant Difference ◽  
Before And After ◽  
Fine Print

✓ The β-endorphin content in cerebrospinal fluid (CSF) was evaluated in 10 patients with idiopathic trigeminal neuralgia during medical treatment (with or without carbamazepine) and after selective thermocoagulation of the Gasserian ganglion. These values were compared with those obtained in a control group of seven patients without pain problems. No statistically significant difference was found between patients suffering from trigeminal neuralgia and those without pain. Furthermore, neither pharmacological treatment nor surgery changed CSF endorphin values. It is concluded that there is no pathogenetic relationship between trigeminal neuralgia and endorphins.

scholarly journals Imaging Experimental Brain Tumors with 1-Aminocyclopentane Carboxylic Acid and Alpha-Aminoisobutyric Acid: Comparison to Fluorodeoxyglucose and Diethylenetriaminepentaacetic Acid in Morphologically Defined Tumor Regions

1997 ◽  
Vol 17 (11) ◽  
pp. 1239-1253 ◽  
Author(s):  
Hisao Uehara ◽  
Tadashi Miyagawa ◽  
Juri Tjuvajev ◽  
Revathi Joshi ◽  
Bradley Beattie ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Brain Tumors ◽  
Vascular Permeability ◽  
Cell Density ◽  
Low Grade ◽  
Acid Uptake ◽  
Diethylenetriaminepentaacetic Acid ◽  
Experimental Brain Tumors ◽  
Walker 256 ◽  
Walker 256 Tumors

The goal of this study was to evaluate the differences and define the advantages of imaging experimental brain tumors in rats with two nonmetabolized amino acids, 1-aminocyclopentane carboxylic (ACPC) acid and α-aminoisobutyric (AIB) acid compared with imaging with fluorodeoxyglucose (FDG) or the gallium-diethylenetriaminepentaacetic acid chelate (Ga-DTPA). 1-aminocyclopentane carboxylic acid, AIB, and FDG autoradiograms were obtained 60 minutes after intravenous injection to simulate positron emission tomography (PET) imaging, whereas the Ga-DTPA autoradiograms were obtained 5 or 10 minutes after injection to simulate gadolinium (Gd)-DTPA–enhanced magnetic resonance (MR) images. Three experimental tumors were studied (C6, RG2, and Walker 256) to provide a range of tumor types. Triple-label quantitative autoradiography was performed, and parametric images of the apparent distribution volume (Va, mL/g) for ACPC or AIB, relative glucose metabolism (R, μmol/100 g/min), vascular permeability to Ga-DTPA (K1, μL/min/g), and histology were obtained from the same tissue section. The four images were registered in an image array processor, and regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images. A comparative analysis of all measured values was performed. The location and morphologic characteristics of the tumor had an effect on the images and measurements of Va, R, and K1. Meningeal extensions of all three tumors consistently had the highest amino acid uptake (Va) and vascular permeability (K1) values, and subcortical portions of the tumors usually had the lowest values. Va and R (FDG) values generally were higher in tumor regions with high-cell density and lower in regions with low-cell density. Tumor areas identified as “impending” necrosis on morphologic criteria consistently had high R values, but little or no change in Va or K1. Tumor necrosis was seen consistently only in the larger Walker 256 tumors; low values of R and Va for AIB (less for ACPC) were measured in the necrotic-appearing regions, whereas K1 was not different from the mean tumor value. The highest correlations were observed between vascular permeability (K1 for Ga-DTPA) and Va for AIB in all three tumors; little or no correlation between vascular permeability and R was observed. The advantages of ACPC and AIB imaging were most convincingly demonstrated in C6 gliomas and in Walker 256 tumors. 1-aminocyclopentane was substantially better than FDG or Ga-DTPA for identifying tumor infiltration of adjacent brain tissue beyond the macroscopic border of the tumor; ACPC also may be useful for identifying low-grade tumors with an intact blood–brain barrier. Contrast-enhancing regions of the tumors were visualized more clearly with AIB than with FDG or Ga-DTPA; viable and necrotic-appearing tumor regions could be distinguished more readily with AIB than with FDG. [11C]-labeled ACPC and AIB are likely to have similar advantages for imaging human brain tumors with PET.

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