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PubMed1984

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

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.

Animals↗
PubMed1986

Establishment and characterization of a cell line from a human gliosarcoma.

A human gliosarcoma culture was characterized from the time of inception to the time of establishment of the cell line (SF-539 BT). Immunohistochemical analysis of the original tumor showed 2 distinct regions of cells. The gliomatous regions were identified by immunostains for glial fibrillary acidic protein and the sarcomatous regions by immunostains for laminin, collagen type IV, procollagen type III, and fibronectin. In early-passage culture, both types of cells maintained their characteristic immunohistochemical profiles; however, after the fourth subcultivation in monolayer culture, no cells expressing glial fibrillary acidic protein could be identified. All cells had become morphologically uniform and expressed laminin, collagen type IV, procollagen type III, and fibronectin only. The immunostaining profile of clones grown in soft agar was similar to that of cells in monolayer culture. At establishment, SF-539 BT has a saturation density of 1.3 X 10(6) cells/25 sq cm, a doubling time of 32 h, and a plating efficiency of 22% in monolayer culture. The tumor cell line is resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, has an abnormal karyotype, grows anchorage independently, and forms a tumor that most closely resembles a spindle cell sarcoma in athymic mice. Its ultrastructure in monolayer culture consists of large cells with an expanded rough endoplasmic reticulum and abundant multivesicular bodies; in athymic mice, extracellular collagen fiber formation is prominent. DEAE-cellulose chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cultures labeled with [3H] proline demonstrated interstitial collagen formation. We conclude that the cell line at establishment is a collagen-producing spindle cell sarcoma that resembles the sarcomatous regions of the original mixed tumor. Further cell separation and characterization studies are needed to determine the pathogenesis of mixed tumors such as gliosarcoma.

Animals↗
PubMed1988

Biological and karyotypic characterization of a new cell line derived from human gliosarcoma.

A cell line (NCE-G28) was established from the biopsy material of a human gliosarcoma of low histological differentiation. The initial cultures showed a mixed population of cells which in later stages became more uniform due to loss of slower growing constituents. The cells have been growing steadily for 20 months. A suspension of NCE-G28 cells injected s.c. as well as i.p. into nude mice produced solid tumors in all cases. Histologically these tumors closely resembled the original tumor. The original tumor, the nude mouse tumor, and NCE-G28 cells were immunochemically positive for glial fibrillary acidic protein as well as for neural plasma membrane antigen A2B5 expression. Two cell strains, 9B2C and 9B2E, were obtained by cloning of the initial cultures and another strain, NCE-G28T, was derived after explantation of a mouse heterotransplant. The two subclones were negative for glial fibrillary acidic protein expression but stained for cell surface fibronectin. NCE-G28T cells initially were positive for glial fibrillary acidic protein but lost this property within 8 months of cultivation. Karyotype analysis of NCE-G28 and the three strains revealed hyperdiploidy and six structurally altered marker chromosomes five of which were shared by nearly all cells. Receptors for epidermal growth factor were detected in all cell lines with the highest levels (about 300,000 receptors/cell) in the parental cell line. The epidermal growth factor receptors had an affinity of 2.5 nM (Kd) and by affinity cross-linking analysis a molecular weight of 170,000 was found. Initially, NCE-G28 cells responded to epidermal growth factor as well as fibroblast growth factor with increased rates of proliferation, while platelet derived growth factor had no effect. In higher passages the growth factor sensitivity was reduced. Using antibodies directed against synthetic protooncogene peptides the production of c-sis immunoreactive material was detected. NCE-G28 cells produce an autocrine factor which stimulated proliferation. This factor is present in conditioned medium and is active on cultured meningiomas and other glioma cell lines. NCE-G28 cells can be maintained in serum-free defined medium on plastic coated with fibronectin or an extracellular matrix from bovine corneal endothelial cells. The NCE-G28 cell line with its strains provide an in vitro model system in which the complexity of gliosarcoma cell populations and the interaction of the cloned cellular constituents can be studied.

Aged↗
PubMed1998

Photodynamic therapy using Photofrin in combination with buthionine sulfoximine (BSO) to treat 9L gliosarcoma in rat brain.

BACKGROUND AND OBJECTIVE: The reactive oxygen mechanisms associated with cell damage after photodynamic therapy (PDT) may be exploited to enhance tumor destruction. Pharmacological reduction of glutathione (GSH), an inhibitor of reactive oxygen species, can be induced by administration of buthionine sulfoximine (BSO). STUDY DESIGN/MATERIALS AND METHODS: BSO was administered in combination with Photofrin as the photosensitizer in order to promote PDT induced cell damage. Photofrin (12.5 mg/kg) or Photofrin with BSO (440 mg/kg) were administered to male Fischer rats (n = 27) containing an intracerebral 9L gliosarcoma or to non tumored rats. Brain tumor or non tumored brain was treated with an optical (632 nm) irradiance of 140 J/cm2. Animals were sacrificed 24 h after PDT and the volume of tissue necrosis was measured. Brain Photofrin concentration was measured in tumor and in non tumor bearing animals administered either Photofrin or Photofrin with BSO. GSH was measured by high pressure liquid chromatography in tumor and homologous non tumor tissue in animals administered BSO or control solution. RESULTS: The volume of tumor necrosis was significantly greater in animals administered Photofrin and BSO than in animals administered only Photofrin. No differences were detected in non tumored tissue damage between groups. No differences in Photofrin concentration were detected in tumored or nontumored animals between animals administered Photofrin and animals administered Photofrin and BSO. BSO administration preferentially and significantly reduced GSH in tumor compared to non tumor tissue. CONCLUSIONS: Our data suggest that BSO administration preferentially augments tumor destruction without compromising non tumored tissue.

Animals↗
PubMed1998

Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays.

Adult-rat-brain tissues display an unusually high resistance to necrosis when serially irradiated with parallel, thin slices of a microplanar (i.e., microscopically thin and macroscopically broad) beam of synchrotron-wiggler-generated, approx. 35-120 keV (median approx. 50 keV) Gd-filtered X rays at skin-entrance absorbed doses of 312 to 5000 Gy per slice. Such microplanar beams were used to irradiate young adult rats bearing right frontocerebral 9L gliosarcomas (approx. 4 mm diameter), through a volume of tissue containing the tumor and contiguous brain tissue, either in a single array or in 2 orthogonally crossed arrays of tissue slices. Each array included 101 parallel microplanar slices, 100 microm center-to-center distance, each slice being approx. 25 microm wide and 12 mm high, with skin-entrance absorbed doses of 312.5 Gy or 625 Gy per slice. Compared with unirradiated controls with a median survival time of 20 days after tumor initiation, the median survival time was extended in irradiated rats by 139 days (625 Gy, crossed arrays), 96 days (312 Gy, crossed arrays) or 24 days (625 Gy, single array). The tumors disappeared in 22 of the 36 irradiated rats, 4/11 even after unidirectional microbeam irradiation. The extent and severity of radiation damage to the normal brain in rats with or without tumor was graded histopathologically. Correlation of those grades with radiation doses shows that loss of tissue structure was confined to beam-crossing regions and that only minor damage was done to zones of the brain irradiated unidirectionally.

Animals↗
PubMed2004

Gliosarcoma: cytopathologic characteristics on fine-needle aspiration (FNA) and intraoperative touch imprint.

Gliosarcoma (GS) is a rare subtype of glioblastoma multiforme (GBM), which shows a dimorphic population of glial and mesenchymal elements. The cytopathology of GS to our knowledge has not been previously described. Although prognostically insignificant within the group of GBM, an accurate recognition of this subtype may help to rule out other morphologically similar primary and metastatic central nervous system (CNS) neoplasms. Thirteen cases of histologically confirmed GS with concomitant touch imprints (TI) or prior fine-needle aspiration (FNA) were retrieved from the files of The Johns Hopkins Hospital (1985-2002). A comprehensive review of the clinico-radiologic, cytologic, and histologic material was undertaken to define the morphologic characteristics of GS. Material was obtained via computerized tomography (CT)-guided needle biopsy. Slides were stained with DiffQuik and/or hematoxylin and eosin (H and E) stains. Smears were highly cellular and showed a high-grade neoplasm with glial and mesenchymal elements. The latter component, however, predominated and showed a variety of phenotypic patterns, which included fibrosarcoma-like, rhabdoid type, osteoclastic giant cell type, undifferentiated type, and tumor with heterologous components (such as chondroid or osteoid tissue). A rich arborizing capillary network was evident, as were a high mitosis/karyorrhexis index and foci of necrosis. The glial component consisted of pleomorphic round to oval nuclei and numerous gemistocytes embedded in a fibrillary stroma.

Adult↗
PubMed1995

Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model.

Camptothecin, a naturally occurring inhibitor of the DNA-replicating enzyme topoisomerase I, demonstrated promising anti-tumor activity in pre-clinical testing; however, because of unexpected toxicity and low anti-tumor effects in the initial clinical trials, further testing was discontinued. We hypothesized that local controlled delivery of camptothecin sodium would achieve effective concentrations in brain tumors without the observed systemic side effects, thereby allowing this novel drug to be used to treat patients with malignant gliomas. To test this hypothesis, we evaluated the sensitivity of rat glioma lines and established human glioma lines to camptothecin in vitro. We found that the LD90 for the established rat and human lines was 0.3 to 1.4 microM after a 1 hr exposure and decreased to less than 0.1 microM after continuous exposure for 7 days. We loaded camptothecin into a controlled-release polymer (ethylene-vinyl acetate co-polymer; EVAc) and showed by high-pressure liquid chromatography that controlled release occurred over at least 21 days. We then tested camptothecin against 9L gliosarcoma, implanted into the brain of Fischer 344 rats. Five days after tumor implantation, animals were treated with camptothecin delivered either systemically or locally by release from EVAc. Local controlled delivery by the polymer significantly extended survival: 59% of the treated animals were long-term survivors (> 120 days) compared to 0% of controls. Systemic administration did not extend survival compared to controls. We compared the efficacy of camptothecin delivered locally with a polymer to camptothecin injected directly into the tumor. Camptothecin increased survival only when delivered locally by polymer.

Animals↗
PubMed1998

In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTPcyclohydrolase I with tyrosine hydroxylase.

To investigate the biochemical requirements for in vivo L-DOPA production by cells genetically modified ex vivo in a rat model of Parkinson's disease (PD), rat syngeneic 9L gliosarcoma and primary Fischer dermal fibroblasts (FDFs) were transduced with retroviral vectors encoding the human tyrosine hydroxylase 2 (hTH2) and human GTP cyclohydrolase I (hGTPCHI) cDNAs. As GTPCHI is a rate-limiting enzyme in the pathway for synthesis of the essential TH cofactor, tetrahydrobiopterin (BH4), only hTH2 and GTPCHI cotransduced cultured cells produced L-DOPA in the absence of added BH4. As striatal BH4 levels in 6-hydroxydopamine (6-OHDA)-lesioned rats are minimal, the effects of cotransduction with hTH2 and hGTPCHI on L-DOPA synthesis by striatal grafts of either 9L cells or FDFs in unilateral 6-OHDA-lesioned rats were tested. Microdialysis experiments showed that those subjects that received cells cotransduced with hTH2 and hGTPCHI produced significantly higher levels of L-DOPA than animals that received either hTH2 or untransduced cells. However, animals that received transduced FDF grafts showed a progressive loss of transgene expression until expression was undetectable 5 weeks after engraftment. In FDF-engrafted animals, no differential effect of hTH2 vs hTH2 + hGTPCHI transgene expression on apomorphine-induced rotation was observed. The differences in L-DOPA production found with cells transduced with hTH2 alone and those cotransduced with hTH2 and hGTPCHI show that BH4 is critical to the restoration of the capacity for L-DOPA production and that GTPCHI expression is an effective means of supplying BH4 in this rat model of PD.

3T3 Cells↗
PubMed2000

Experimental gliosarcoma induces chemokine receptor expression in rat brain.

Macrophage/microglial infiltration is a characteristic feature of brain tumors. The functional role(s) of these cells is complex and could include both trophic and suppressive effects on tumors. Information has recently emerged about the molecular signals that regulate the accumulation and function of monocytes in pathological disorders. Recent data indicate that the chemokine, monocyte chemoattractant protein-1 (MCP-1), a potent monocyte activating and chemotactic factor, is a primary regulator of the macrophage response in brain tumors. We hypothesized that if MCP-1 regulates macrophage/microglial infiltration, then expression of the specific MCP-1 receptor, CCR2, will be induced in peritumoral tissue and/or within brain tumors. Identification of a specific receptor that is preferentially expressed in brain tumors could be important both in terms of tumor biology and as a potential therapeutic target. We used an established experimental gliosarcoma model, induced by intracranial transplantation of cultured 9L cells into adult rat brain, to test this hypothesis. RT-PCR analysis showed high levels of both MCP-1 and CCR2 mRNA and Western blot analysis demonstrated increased CCR2 protein in tumor extracts. Immunocytochemistry showed CCR2 immunoreactive microglia in peritumoral tissue and, unexpectedly, that intrinsic tumor cells, rather than monocytes, were the predominant source of CCR2. These results demonstrate that CCR2 expression is markedly upregulated in this brain tumor model.

Animals↗
PubMed1993

Suppression of 9L gliosarcoma growth by copper depletion with copper-deficient diet and D-penicillamine.

Trace element such as Cu and Zn have important chemical and biological properties. Recently, tissue Cu and Zn concentrations have been correlated with prognosis in selected malignancies. In addition, depletion of trace metals has suppressive effects on tumor growth in experimental rat models. We measured tissue levels of Cu and Zn and investigated the inhibitory effects on tumor growth in a rat brain tumor model by the Cu-depletion. 9L gliosarcoma cells were injected subcutaneously in 24 anesthetized 5 week old male Fischer-344 rats. Control animals (n = 12) were given a normal diet throughout the experiment and hypocupremic rats (n = 12) were given a Cu-deficient diet beginning 3 weeks before and after tumor implantation, and administered 2 mg of D-Penicillamine peri os., once daily, 3 days before and after implantation. At the time of sacrifice, samples were taken to measure tumor weights. To determine tissue Cu and Zn levels, atomic absorption spectrophotometry was used. Cu, Zn and Cu/Zn ratio were significantly higher in control tumors than brain tissues. Cu levels and Cu/Zn ratio were significantly lower in hypocupremic tumors than those in control tumors. Zn levels in hypocupremic tumors were significantly higher than control tumors. Our study indicated that Cu depletion by a Cu-deficient and D-Penicillamine reduced Cu concentration and Cu/Zn ratio in a tumor model with reduction of tumor weight. A metabolic approach that restricts Cu to alter the microenvironment within the cell must become a new horizon of cancer therapy.

Animals↗
PubMed1994

A rat glioma model, CNS-1, with invasive characteristics similar to those of human gliomas: a comparison to 9L gliosarcoma.

A glioma cell line, CNS-1, was developed in the inbred Lewis rat to obtain a histocompatible astrocytoma cell line with infiltrative and growth patterns that more closely simulate those observed in human gliomas. Rats were given weekly intravenous injections for a six month period with N-nitroso-N-methylurea to produce neoplasm in the central nervous system. Intracranial tumor was isolated, enzymatically and mechanically digested, and placed into culture. The tumor cell line injected subcutaneously on the flanks of Lewis rats grew extensively in situ as cohesive tumor masses but did not metastasize. Intracranially, CNS-1 demonstrated single cell infiltration of paranchyma and leptomeningeal, perivascular, and periventricular spread with expansion of the tumor within choroid plexus stroma. CNS-1 cells titrated in right frontal brain of Lewis rats at 10(5), 5 x 10(5), 10(5), 5 x 10(4) cells per group had mean survival times ranging from 20.5 to 30.2 days. CNS-1 was immunoreactive for glial fibrillary acidic protein, S100 protein, vimentin, neural cell adhesion molecule, retinoic acid receptor alpha, intercellular adhesion molecule, and neuron specific enolase. The CNS-1 cells commonly had one or more trisomies of chromosomes 11, 13 or 18; losses, possibly random, of chromosomes (3, 5, 19, 30, X or Y) were noticed, and a marker chromosome made up of approximately 3 chromosomes was usual. Comparisons of CNS-1 to 9L gliosarcoma tumor were made. The glial CNS-1 tumor model provides an excellent system in which to investigate a variety of immunological therapeutic modalities. It spreads within brain in a less cohesive mass than 9L and is accepted without rejection in non-central nervous system sites by Lewis rats.

Animals↗
PubMed1993

Relationship of perfusion to edema in the 9L gliosarcoma.

The relationship between tumor perfusion and edema was analyzed, with edema characterized as tumor wet/dry weight ratio. Perfusion of subcutaneous 9L gliosarcoma was measured by injection of 133Xe in saline into the tumor core, followed by gamma camera imaging of 133Xe washout kinetics. A significant inverse correlation was found between edema and tumor perfusion (p < 0.0002), suggesting that edema can limit tumor perfusion, perhaps through a mechanism of increased interstitial fluid pressure. The perfusion rate of highly edematous tumors was reduced to less than 10% of the perfusion rate of less edematous tumors (p < 0.001). It was also found that tumor edema increased significantly with increasing tumor volume (p < 0.001), which could account for the finding that perfusion declined significantly with increasing tumor volume (p < 0.02). These findings are potentially important because it is possible to quantify tumor edema in vivo, with millimeter resolution, using 1H magnetic resonance imaging (MRI). Thus MRI may provide a non-invasive technique for characterizing tumor perfusion or tumor drug delivery.

Animals↗
PubMed1998

Gliosarcoma with angiosarcomatous features: a case report.

A surgical case of gliosarcoma in which the mesenchymal component showed angiosarcomatous features is reported. The neoplasm was extirpated from the right cerebral hemisphere of a 76-year-old man who presented with left hemiparesis and headache, and it was composed of both anaplastic astrocytomatous and sarcomatous elements. The sarcomatous element was composed of a proliferation of atypical endothelial cells that had pleomorphic, mitotically active nuclei and formed vascular lumina of irregular shapes or solid cellular sheets, and was accompanied by the deposition of collagenous matrix. The cytoplasm of some of the atypical endothelial cells was immunohistochemically positive for vimentin, factor VIII-related antigen, CD 34, and thrombomodulin. The MIB-1 labeling index of the sarcomatous component was higher than that of the astrocytomatous component.

Aged↗
PubMedDate not supplied

Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo.

Immunotherapy of gliomas has been forwarded as an attractive alternative to standard therapeutic modalities. Numerous observations indicate some therapeutic efficacy with this approach, but it is not curative in most reports. It is well established that gliomas suppress immune reactivity via a number of mechanisms, including expression CD95 ligand (CD95L), which induces apoptosis of immune effector cells, and secretion of immunosuppressive factors such as transforming growth factor-beta (TGFbeta). It has been hypothesized that abrogation of production or function of TGFbeta would improve immune reactivity to gliomas. To investigate this in a fashion that is translatable into clinical practice, we utilized a retroviral vector encoding a truncated, soluble form of the Type II receptor for TGFbeta (TFGbeta sr) and expressed it in the rat 9L gliosarcoma line (9L-TGFbeta sr). We then determined whether expression of TGFbeta sr affected in vitro sensitivity of 9L to lysis by immune effector cells, whether expression of TGFbeta sr affected tumorigenesis of 9L in vivo, and whether TGFbeta sr affected expression of immunity to 9L. In these experiments, we determined that 9L-TGFbeta sr was more susceptible than sham transfected 9L (9L-neo) to lysis by natural killer (NK) cells. We also determined that subcutaneously implanted 9L-TGFbeta sr was less tumorigenic than 9L-neo in syngeneic rats. Similarly, survival was extended by approximately 40% in rats given intracranial 9L-TGFbeta sr compared to 9L-neo. Finally, we determined that elimination of CD161+ cells resulted in comparable growth of 9L-neo and 9L-TGFbeta sr in vivo, indicating that NK or NK-like cells were responsible for the anti-tumor effects in this model.

Animals↗
PubMed2001

Postradiation gliosarcoma with osteosarcomatous components.

A 49-year-old man developed a gliosarcoma with prominent osteoid components 15 months after surgical resection and postoperative radiation and chemotherapy for a right frontal glioblastoma multiforme. The recurrent tumor was distinguished from the original lesion by the presence of dense ossification, visible on CT, at the original tumor site. The relevant literature is reviewed.

Brain Neoplasms↗
PubMed1996

Gliosarcoma developing from an irradiated ependymoma.

A 17-year-old girl was operated for a cystic mass located deep within the left parieto-occipital white matter. Histologically the tumor was an ependymoma with a vascular stroma. In spite of irradiation the tumor recurred locally twice, 1 and 2 years respectively after the original operation. The ependymoma portion of the tumor remained unchanged, but the stroma showed increased vascular hyperplasia at the time of the second operation and transformation into a fibrosarcoma in the third operative specimen. Proliferating cell markers (MIB-1) were positive only in the ependymoma cell nuclei in the first two specimens, but were also extensively present in the nuclei of the fibrosarcoma in the third specimen. In the latter, the fibrosarcoma portion greatly overwhelmed the residual ependymoma islands, but remained sharply delineated from them. This is the first observed case of a gliosarcoma originating from an ependymoma. The histological pattern of this mixed tumor clearly indicates that the source of the sarcomatous portions was the neoplastically transformed fibrovascular stroma of the original tumor, rather than "desmoplastic" alterations of the neoplastic ependymal cells themselves.

Adolescent↗
PubMed2005

Multi-focal gliosarcoma: a case report and review of the literature.

Gliosarcoma (GS) is an uncommon malignant brain tumor with biphasic tissue pattern consisted of both glial and sarcomatous components. It usually occurs in adult population of middle age. We report a rare case of multi-focal GS that was initially interpreted as metastases of extra-cranial tumor. The histological examination revealed the biphasic pattern of a GS. The patient was treated with postoperative external radiation therapy and had poor prognosis. To our knowledge this is the second published case of GS with multi-focal presentation. In this study we also review the literature on clinicopathological aspects of GS.

Brain Neoplasms↗