Interstitial laser photochemotherapy of rhodamine-123-sensitized rat glioma

1987 ◽  
Vol 67 (6) ◽  
pp. 889-894 ◽  
Author(s):  
Stephen K. Powers ◽  
William C. Beckman ◽  
J. Tony Brown ◽  
Linda C. Kolpack
Keyword(s):  
Laser Light ◽  
Malignant Gliomas ◽  
Argon Laser ◽  
Rhodamine 123 ◽  
Adult Rats ◽  
Content Type ◽  
Rat Glioma ◽  
Original Tumor ◽  
Interstitial Laser

✓ The effect of interstitial laser photochemotherapy with the mitochondrial-specific intravital dye rhodamine-123 (Rh-123) was studied using a malignant rat glioma model system (RT2). Tumors were transplanted subcutaneously into the flank of athymic mice and into the cerebrum of adult rats. The Rh-123 photosensitization was produced by direct intratumoral injection of Rh-123 into the mouse RT2 flank tumors and by intravenous Rh-123 administration to adult rats with implanted RT2 intracerebral tumors. Intratumoral irradiation with 150 mW of argon laser light for an exposure time of 15 minutes was performed using a conical sapphire-tipped quartz optical fiber. Control groups of animals received either no treatment, Rh-123 injections, or administration of 150 mW of argon laser light for 15 minutes. Both flank and intracerebral tumors showed progressive diminution in size after treatment with Rh-123 photochemotherapy. There was no evidence of tumor recurrence in 60% of Rh-123 photochemotherapy-treated tumors. Recurrences in tumors treated with Rh-123 photochemotherapy usually appeared at the periphery of the original tumor at 10 days after treatment. Histologically, photochemotherapy-treated intracerebral tumors showed progressive shrinkage with increasing tumor necrosis over time. The finding of residual or recurrent tumor at the periphery of the original tumor mass suggests that the lack of penetration of the blue-green (argon) light was responsible for preventing complete tumor ablation. Our results suggest that Rh-123 photochemotherapy can destroy malignant gliomas in vivo; however, the poor penetrability of the photoactivating blue-green light may limit the effectiveness of this treatment for large or extensively invasive tumors.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

scholarly journals Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

2014 ◽  
Vol 120 (4) ◽  
pp. 854-863 ◽  
Author(s):  
Kaleb Yohay ◽  
Betty Tyler ◽  
Kyle D. Weaver ◽  
Andrea C. Pardo ◽  
Dan Gincel ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Malignant Gliomas ◽  
In Vitro Assays ◽  
Systemic Delivery ◽  
Organotypic Cultures ◽  
9L Gliosarcoma ◽  
Rat Glioma ◽  
F98 Glioma

Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

Measurements of argon laser light attenuation in the skin 'in vivo' using a unique animal model

2003 ◽  
Author(s):  
Z.F. Gourgouliatos ◽  
S. Ghaffari ◽  
A.J. Welch ◽  
K.R. Diller ◽  
R.C. Straight
Keyword(s):  
Animal Model ◽  
Laser Light ◽  
Light Attenuation ◽  
Argon Laser

Synergism between BCNU and irradiation in the treatment of anaplastic gliomas

1979 ◽  
Vol 51 (5) ◽  
pp. 581-586 ◽  
Author(s):  
Paul Steinbok ◽  
M. Stephen Mahaley ◽  
Raymond U ◽  
Douglas C. Zinn ◽  
Stan Lipper ◽  
...  
Keyword(s):  
Median Survival ◽  
Combined Therapy ◽  
Malignant Gliomas ◽  
Control Group ◽  
Therapeutic Effects ◽  
Survival Times ◽  
Content Type ◽  
Anaplastic Gliomas ◽  
In Series

✓ The therapeutic effects of irradiation, BCNU, or combined irradiation and BCNU were studied in the avian sarcoma virus (ASV)-induced glioma model in rats. Whole-head orthovoltage radiation therapy was given in six equal fractions over 2 weeks, and BCNU was administered intraperitoneally as a single dose of 10 mg/kg. Two series of experiments were performed in order to duplicate the results. In Series 1, the median survival times of the experimental groups, in days after randomization, were as follows: control group (no treatment), 69; group receiving 2000 rads, 84 (p < 0.05); group receiving BCNU, 80.5 (p < 0.1); and group receiving 2000 rads + BCNU, 112 (p < 0.001). In Series 2, the median survival times were: control group, 73.5; group receiving 2300 rads, 85 (p < 0.01); group receiving BCNU, 92.5 (p < 0.025); and group receiving 2300 rads + BCNU, 123.5 (p < 0.001). In both series, combined therapy was significantly better than either radiation or BCNU alone. This is the first time that a synergistic effect of BCNU and irradiation has been reported in an in vivo brain-tumor model and supports the clinical use of this combination in the treatment of malignant gliomas.

Chemotherapeutic trials on human malignant astrocytomas in organ culture

1977 ◽  
Vol 46 (3) ◽  
pp. 320-327 ◽  
Author(s):  
Ruben J. Saez ◽  
R. Jean Campbell ◽  
Edward R. Laws
Keyword(s):  
Organ Culture ◽  
Malignant Gliomas ◽  
Three Dimensional ◽  
Drug Effects ◽  
Porous Matrix ◽  
Pharmacological Management ◽  
Content Type ◽  
Malignant Astrocytomas ◽  
The Matrix

✓ A technique of organ culture based on a three-dimensional porous matrix was employed for chemotherapeutic trials on human malignant astrocytomas. This method allows neoplasms to retain the morphological identity and the histological characteristics they possess in vivo. Success in culture was greatest with high-grade astrocytomas, the majority of which showed definite infiltration of the matrix. Lowgrade tumors, if viable, did not display active penetration. Drug trials on eight malignant astrocytomas included BCNU, methyl CCNU, VP 16–213, and Solu-Medrol. Cyanide and luciferase were used as experimental metabolic toxins. Evidence of cytotoxicity was assessed qualitatively by histological changes on microscopic preparations of treated and control cultures. Microfluorometric determinations of reduced nicotinamide adenine dinucleotide (NADH) were applied to these trials in an effort to detect a quantitative biochemical index of drug effects. A variable rise in mean NADH levels above controls was recorded from the majority of treated cultures although correlation with microscopic changes was inconsistent. Because of its potential merits, organ culture may be a valuable tool for further work on pharmacological management of malignant gliomas.

Cerebral metabolism in experimental hydrocephalus: an in vivo 1H and 31P magnetic resonance spectroscopy study

1999 ◽  
Vol 91 (4) ◽  
pp. 660-668 ◽  
Author(s):  
Kees P. J. Braun ◽  
Pieter van Eijsden ◽  
W. Peter Vandertop ◽  
Robin A. de Graaf ◽  
Rob H. J. M. Gooskens ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Magnetic Resonance ◽  
Mr Spectroscopy ◽  
Neuronal Damage ◽  
Lactate Production ◽  
Cerebral Damage ◽  
Adult Rats ◽  
Content Type ◽  
Fine Print

Object. Brain damage in patients with hydrocephalus is caused by mechanical forces and cerebral ischemia. The severity and localization of impaired cerebral blood flow and metabolism are still largely unknown. Magnetic resonance (MR) spectroscopy offers the opportunity to investigate cerebral energy metabolism and neuronal damage noninvasively and longitudinally. Previous 1H MR spectroscopy studies have shown an increased lactate resonance that is suggestive of anaerobic glycolysis. The aim of this study was to assess cerebral damage and energy metabolism in kaolin-induced hydrocephalus in adult rats by using in vivo 1H and 31P MR spectroscopy. The presence of lactate was correlated with high-energy phosphate metabolism and intracellular pH. The measurement of relative concentrations of N-acetyl aspartate (NAA), choline (Cho), and total creatine (tCr) served to assess neuronal damage.Methods. Hydrocephalus was induced in adult rats by surgical injection of kaolin into the cisterna magna. Magnetic resonance studies, using a 4.7-tesla magnet, were performed longitudinally in hydrocephalic animals at 1 (10 rats), 8 (six rats), and 16 weeks (six rats) thereafter, as well as in eight control animals. To evaluate ventricular size and white matter edema T2-weighted MR imaging was performed. The 1H MR spectra were acquired from a 240-µl voxel, positioned centrally in the brain, followed by localized 31P MR spectroscopy on a two-dimensional column that contained the entire brain but virtually no extracranial muscles. The 1H and 31P MR spectroscopy peak ratios were calculated after fitting the spectra in the time domain, intracellular pH was estimated from the inorganic phosphate (Pi) chemical shift, and T2 relaxation times of 1H metabolites were determined from the signal decay at increasing echo times.Conclusions. In hydrocephalic rats, ventricular expansion stabilized after 8 weeks. White matter edema was most pronounced during acute hydrocephalus. Lactate peaks were increased at all time points, without a decrease in phosphocreatine (PCr)/Pi and PCr/adenosine triphosphate (ATP) peak ratios, or pH. Possibly lactate production is restricted to periventricular brain tissue, followed by its accumulation in cerebrospinal fluid, which is supported by the long lactate T2 relaxation time. Alternatively, lactate production may precede impairment of ATP homeostasis. The NAA/Cho and tCr/Cho ratios significantly decreased during the acute and chronic stages of hydrocephalus. These changes were not caused by alterations in metabolite T2 relaxation time. The decreases in the NAA/Cho and tCr/Cho ratios implicate neuronal loss/dysfunction or changes in membrane phospholipid metabolism, as in myelin damage or gliosis. It is suggested that 1H MR spectroscopy can be of additional value in the assessment of energy metabolism and cerebral damage in clinical hydrocephalus.

Expanded spectrum of viral therapy in the treatment of nervous system tumors

1992 ◽  
Vol 77 (4) ◽  
pp. 590-594 ◽  
Author(s):  
James M. Markert ◽  
Donald M. Coen ◽  
Amy Malick ◽  
Toshihiro Mineta ◽  
Robert L. Martuza
Keyword(s):  
Cell Culture ◽  
Nervous System ◽  
Malignant Gliomas ◽  
Treated Group ◽  
Early Passage ◽  
Content Type ◽  
Nervous System Tumors ◽  
Viral Therapy ◽  
Subrenal Capsule

✓ Despite aggressive therapy, many nervous system neoplasms, including malignant gliomas, medulloblastomas, malignant meningiomas, and neurofibrosarcomas, maintain high mortality rates. The authors recently utilized a thymidine kinase-negative herpes simplex-1 mutant virus, dlsptk, with reduced neurovirulence, for the effective treatment of malignant human gliomas in cell culture and in nude mouse in vivo models. The range of human nervous system tumors that might be responsive to viral therapy is now expanded. Three medulloblastoma, four malignant or atypical meningioma, and five neurofibrosarcoma cell lines or early-passage tumors were treated with the dlsptk virus in cell culture. A cell death rate of at least 99% was evident in every tumor tested for at least one multiplicity of infection within 14 days after treatment. Control tumor cell cultures remained viable. To test dlsptk therapy in vivo, the authors treated human medulloblastoma subcutaneous xenografts with two doses of dlsptk. Mean growth ratios were significantly inhibited in the treated group when compared to control tumors, and there was a significant number of tumor regressions in the treated animals. Similar results were seen with human malignant meningioma xenografts in a subrenal capsule study. These results encourage the further investigation of viral therapy in the treatment of a broad spectrum of nervous system tumors refractory to conventional treatment methods.

Multicellular tumor spheroids from human gliomas maintained in organ culture

1990 ◽  
Vol 72 (3) ◽  
pp. 463-475 ◽  
Author(s):  
Rolf Bjerkvig ◽  
Audun Tønnesen ◽  
Ole Didrik Laerum ◽  
Erik-Olof Backlund
Keyword(s):  
Tumor Tissue ◽  
Proliferative Potential ◽  
Ultrastructural Observation ◽  
Tumor Spheroids ◽  
Human Gliomas ◽  
Proliferating Cells ◽  
Content Type ◽  
Original Tumor ◽  
Fine Print

✓ Tumor tissue from seven human gliomas was maintained in long-term agar overlay culture as multicellular organotypic spheroids. Light microscopic and ultrastructural observation of the spheroids displayed morphological features similar to those of the original tumor tissue in vivo; in this respect they were different from spheroids obtained from permanent cell lines. The spheroids contained preserved vessels, connective tissue, and macrophages, revealing a close resemblance to the conditions in the original tumor. Flow cytometric deoxyribonucleic acid measurements of cells from the tumor spheroids and from biopsy material obtained directly from the operation revealed the same ploidy and the same amount of proliferating cells in the spheroids as in the original tumor. Fluorescence microscopy using bromodeoxyuridine (BUdR) incorporation and anti-BUdR monoclonal antibody confirmed the proliferative potential of tumor cells in the spheroids. Diameter measurements showed that the size of the spheroids from two of the tumors increased over time while in three other cases it decreased. Spheroids from the remaining two tumors showed no change in size, even after 80 days in culture. These growth data and the relatively high number of proliferating cells, as measured by flow cytometry, indicate that the degree of cell proliferation and cell loss from the spheroids are closely linked, as is the case for tumors in vivo. The culture system presented provides a valuable alternative to propagation of human tumors in animals.

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.

Measurements of argon laser light attenuation in the skin ‘in vivo’ using a unique animal model

1992 ◽  
Vol 7 (1-4) ◽  
pp. 63-71 ◽  
Author(s):  
Zafirios F. Gourgouliatos ◽  
Ashley J. Welch ◽  
Kenneth R. Diller
Keyword(s):  
Animal Model ◽  
Laser Light ◽  
Light Attenuation ◽  
Argon Laser
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