Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigates a new approach to adoptive therapy of glioblastoma using as antitumor effector a potent major histocompatibility complex nonrestricted killer clone (TALL-104) established from a patient with acute T-lymphoblastic leukemia. The human glioblastoma cell line U-87 MG could be successfully engrafted in mice with severe combined immunodeficiency using the i.p., intracerebral, and s.c. routes. The latter model was elected to evaluate therapy based on its high reproducibility. Tumor growth in mice engrafted s.c. was proportionally associated with splenomegaly and leukocytosis. Multiple transfers of lethally irradiated (non-proliferating) TALL-104 cells at the tumor site resulted in about 50-70% inhibition of tumor growth as compared to untreated mice, with concomitant reduction of splenomegaly and leukocytosis. The antitumor effects were inversely proportional to the size of the tumor at initiation of therapy, 90-100% inhibition occurring in severe combined immunodeficiency mice treated from the day of U-87 MG challenge. Neither splenomegaly nor leukocytosis developed in animals in which tumor growth was completely blocked. Stimulation of TALL-104 cells with either interleukin 2 or interleukin 12 prior to irradiation and adoptive transfer increased the antitumor efficacy of the killer cells to about the same extent. The potential usefulness of irradiated TALL-104 cells in adjuvant therapy against glioblastomas and other well-localized tumors is discussed.
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PMID:Treatment of experimental glioblastoma with a human major histocompatibility complex nonrestricted cytotoxic T cell line. 780 48

A total of 22 surgical specimens, 16 astrocytomas with various malignancy, 3 brains adjacent to tumor and 3 brains with non-neoplastic lesion, was investigated immunohistochemically for the expression of thrombomodulin (TM). This membrane protein is localized on the vascular endothelium of nearly every human tissue and plays a crucial role in the maintenance of antithrombotic property of the endothelial cells. Although the normal cerebral vessels were negative for TM, the tumor vessels were positive for TM. The increased expression of TM was, however, demonstrated not only in glioblastomas but also in low-grade astrocytomas. Furthermore, the vessels in the brains adjacent to tumor and gliotic brains were also positive for TM. Those observations suggested that the tendency of intratumoral bleeding, which is rather characteristic of glioblastomas, is not simply explained by the altered expression of vascular endothelial TM. In two cases of glioblastoma, not only the blood vessels but also the tumor cells were positive. Considering the mitogenic activity of thrombin, a ligand for TM, the increased expression of TM might be related to the tumor neovascularization and also the tumor growth.
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PMID:Expression of thrombomodulin in astrocytomas of various malignancy and in gliotic and normal brains. 796 91

Temozolomide, a methylating agent with clinical activity against brain tumors, demonstrated excellent antitumor activity following p.o. administration to athymic mice bearing human brain tumor xenografts. In the early stage s.c. implanted SNB-75 astrocytoma model, a 400-mg/kg dose administered on Day 5 produced 10 of 10 Day 54 tumor-free mice. In later staged s.c. U251 and SF-295 glioblastoma models, a single 600-mg/kg dose produced 9 of 10 Day 86 and 2 of 10 Day 40 tumor-free mice, respectively. In the latter group, a tumor growth delay of > 315% was attained. Similar levels of activity were attained with equal total doses on schedules of daily for 5 doses and every fourth day for 3 doses. A single 40-mg/kg i.v. dose of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) also demonstrated excellent activity, producing 9 of 10 tumor-free mice in the SNB-75 model and growth delays of 283 and 301% in the U251 and SF-295 models, respectively. Temozolomide was also highly effective against intracerebral implants of the U251 and SF-295 glioblastomas. Administration of either 600 mg/kg on Day 1 or 200 mg/kg on Days 1, 5, and 9 produced 7 of 9 Day 90 tumor-free mice in the U251 model. In the SF-295 model, a single 400-mg/kg dose or three 200-mg/kg doses produced 3 and 4 of 10 Day 90 tumor-free mice, respectively, and prolonged survival by 127%. A single 40-mg/kg i.v. dose of BCNU was more effective than temozolomide in the intracerebral SF-295 model, and less effective in the intracerebral U251 model. The synergistic potential of temozolomide and BCNU in combination was evaluated in an advanced stage s.c. implanted SF-295 model. When temozolomide was administered 2 h after BCNU on a single treatment day, a dramatic synergistic therapeutic effect was observed in two experiments. For example, single agent doses of temozolomide (600 mg/kg) and BCNU (60 mg/kg) and a combination (400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced growth delays of 190, 258, and > 492% (includes 5 of 10 Day 51 tumor-free mice), respectively. Analysis of the data by a quadratic dose response model indicated synergism with significance at P = 0.0001 in both experiments. Synergism also was demonstrated by the isobole method. The reverse sequence was more toxic, but at lower combination doses a synergistic effect was still observed (P = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. 803 99

We have demonstrated that attenuated mutants of herpes simplex virus (HSV) have therapeutic potential for malignant brain tumors. In this report, we tested a ribonucleotide reductase-deficient (RR-) HSV mutant as an experimental treatment for malignant brain tumors. The HSV-RR- mutant hrR3, containing an Escherichia coli lacZ gene insertion in the ICP6 gene that encodes the large subunit of RR, was used in this study. We examined the cytopathic effect of hrR3 (0.1 plaque-forming unit/cell) on the U-87MG human glioblastoma cell line in vitro. Only 0.2% of U-87 cells were alive 67 h postinfection. Drug sensitivity assays demonstrated that hrR3 is hypersensitive to the antiherpetic agent ganciclovir. For in vivo studies, 10 animals harboring U-87MG tumors were randomly divided and treated intraneoplastically with either 5 x 10(6) plaque-forming units of hrR3 or medium alone. The viral treatment group showed significant inhibition of tumor growth (P < 0.01; one-sided Wilcoxon rank test). Expression of the lacZ gene in hrR3, visualized by 5-bromo-4-chrolo-3-indolyl-beta-D-galactopyranoside histochemistry, could be detected in treated tumors. The therapeutic potential of this HSV-RR- mutant for malignant gliomas is discussed.
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PMID:Treatment of malignant gliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant. 803 22

Glioblastoma is the most malignant primary brain tumor. Inhibition of angiogenesis is one potential strategy for treating this fatal hypervascular tumor. AGM-1470 (also called TNP-470), a novel, potent, fungus-derived inhibitor of angiogenesis, was tested on the growth of human glioblastoma cells in culture and on the growth of the tumor in nude mice. In nude mice with subrenally implanted U-87 MG glioblastomas, AGM-1470 significantly inhibited tumor growth (P < 0.01), and in nude mice with intracranial U-87 MG glioblastomas, AGM-1470 prolonged survival. In addition to its expected action as an angiogenesis inhibitor, AGM-1470 also directly inhibited U-87 MG cells in culture at concentrations similar to those that inhibited endothelial cells. The combined inhibition of glioblastoma cell mitosis and of glioblastoma-induced neovascularization suggests that AGM-1470 should be considered for further investigation in the treatment of this fatal tumor.
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PMID:AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. 805 85

Targeted protein toxins are a new class of reagents with the potential for great tumor selectivity and cytotoxic potency. Two such compounds were studied: 1) Tf-CRM107, a conjugate of human transferrin (Tf) and diphtheria toxin with a point mutation (CRM107); and 2) 454A12-rRA, a conjugate of a monoclonal antibody (454A12) to the human Tf receptor and recombinant ricin A chain (rRA). Both compounds are potent and specific in killing human glioblastoma cell lines in vitro. The authors investigated the activity of these reagents administered intratumorally against solid U251 MG human gliomas in vivo. Nude mice with established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were randomly assigned to be treated with 100-microliters intratumoral injections of Tf-CRM107 (10 micrograms) or 454A12-rRA (10 micrograms), equimolar doses of CRM107 (4.3 micrograms), 454A12 antibody (7.5 micrograms), or rRA (1.5 micrograms), or phosphate-buffered saline (PBS) every 2 days for a total of four doses. Tumor volume and animal weight were assessed by a blinded observer before each treatment and biweekly for 30 days after initiating therapy. With Tf-CRM107 administration, tumor regression of greater than 95% occurred by Day 14 (p < 0.01) and tumors did not recur by Day 30. Treatment with 454A12-rRA caused a 30% decrease in tumor volume by Day 14 (p < 0.01). Treatment with equimolar doses of the unconjugated targeted protein toxin components CRM107, 454A12, or rRA caused significant U251 MG tumor growth inhibition, but the effects were less potent than the antitumor effects of the conjugates. This study also characterized the dose-response effect of Tf-CRM107 on tumor growth and tumor weight on Day 30. Nude mice with established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were treated with 100-microliters intratumoral injections of 10, 1.0, or 0.1 microgram of Tf-CRM107 or PBS every 2 days for a total of four doses. All three doses of Tf-CRM107 significantly inhibited tumor growth by Day 14 (p < 0.01) and at Day 30 (p < 0.05), with a significant dose-response relationship. This study demonstrated in vivo efficacy of the targeted toxins Tf-CRM107 and 454A12-rRA against a human glioma. With intratumoral administration, the effect of Tf-CRM107 was tumor-specific and in some animals curative. Regional therapy with these potent tumor-specific agents using direct intratumoral infusion should limit systemic toxicity and may be efficacious against brain tumors.
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PMID:Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. 811 65

A 56-year-old man is reported who had suffered a frontal, frontobasal open craniocerebral injury four years ago. He presented for treatment with a glioblastoma of which the location and extent precisely corresponded to that of the prior brain injury. After surgical exposure of the tumor, we had the impression that the tumor initially showed granulating growth from the frontal injury site and had then given rise to more highly vascularized and also necrotizing tumor tissue spreading into the frontal medullary layer with typical glioblastoma characteristics. In view of the surgical site, it is logical to consider a tumorigenesis after cerebral trauma, which is also corroborated by the histological results, since more proliferative tumor growth was found near to the injury and more highly vascularized but also necrotizing (i.e. more typical of a glioblastoma) tumor growth far away from the injury. After the comparison of our observation with the corresponding cases in the literature, it is shown that there is at least in part a causal correlation between the trauma and tumorigenesis: in the previously healthy patient, the tumor developed precisely in the region of the injury (with detection of destroyed brain tissue) after a sufficiently long time interval. Near to the site of damage, it showed granulative growth with a low degree of vascularization, and then passed into the typical glioblastoma. Observations of genetic changes in glioblastoma patients is not inconsistent with this possible trauma genesis, but render it probable that trauma is the factor which can give rise to tumor growth in a corresponding susceptibility to tumorigenesis.
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PMID:[The traumatic origin of a glioblastoma]. 812 88

Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) are potent mitogens for normal cells of ectodermal and mesodermal origin. Evidence is accumulating that suggests that EGF, TGF alpha and their common receptor (EGF/TGF alpha-R) influence development and functioning of tissues of the central nervous system (CNS). To further investigate the possible roles of EGF, TGF alpha and their receptor in autocrine/paracrine regulation of tumor growth in the CNS, a series of tumors of the CNS were analyzed for the presence of specific, high affinity EGF/TGF alpha receptors and for the presence of immunoreactive TGF alpha protein. Binding of 125I-EGF to crude membranes from a pool of meningiomas was competed for equally well by low concentrations of unlabeled EGF or TGF alpha, but not by high concentrations of other protein hormones, demonstrating the high degree of specificity of the EGF/TGF alpha receptor. Specific binding of 125I-EGF was dependent upon time and temperature, with maximum specific binding achieved after two hours at 22 degrees C. Scatchard analysis of six tumors of the CNS large enough to permit titration analysis generated linear plots with an average kilodalton of 1.1 +/- 0.1 nanometer (+/- standard error of the mean), suggesting the presence of a single class of EGF/TGF alpha-R with high affinity. EGF also stimulated phosphorylation of a 170 kilodalton protein in membrane fraction of a meningioma, demonstrating that the EGF/TGF alpha-R in this tumor retained EGF-stimulated kinase autophosphorylating activity. Membranes for 17 additional smaller tumors of the CNS were analyzed for specific binding of 125I-EGF by single, high concentration method, and all 17 tumors were found to contain specific binding of 125I-EGF. The average level of 125I-EGF for all 23 tumors of the CNS was 46 +/- 27 femtomoles per milligram protein with a range of 1 femtomoles per milligram for both a pituitary adenoma and meningioma to 638 femtomoles per milligram for a glioblastoma. A series of 13 tumors of the CNS were analyzed for EGF alpha with use of a specific radioimmunoassay. TGF alpha immunoreactive protein was detected in all four malignant tumors of the CNS assayed at an average level of 2.6 +/- 1.1 nanograms per milligram soluble protein, whereas TGF alpha immunoreactive protein was detected in only two of nine benign tumors of the CNS. These results add support to the hypothesis that TGF alpha and its receptor may act by autocrine/paracrine mechanisms to influence growth of tumors of the CNS in vivo.
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PMID:Detection of epidermal growth factor and transforming growth factor alpha protein in meningiomas and other tumors of the central nervous system in human beings. 821 1

Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.
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PMID:Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. 831 77

The effect of 7 beta-hydroxycholesteryl-3-oleate on rat brain C6 glioblastoma cells was studied. Three days after the inoculation of 2 x 10(5) C6 cells into the frontal cortex of 6-day-old Wistar rats, two types of liposomes [consisting of either phosphatidylcholine and monosialoganglioside (PG:GM1, 10:1 mol/mol) only, or containing 7 beta-hydroxycholesterol, 7 beta-hydroxycholesteryl-3-oleate, 7 alpha-hydroxycholesteryl-3-oleate, or 7-ketocholesteryl-3-oleate] were injected into the xenograft. Ten days later, the animals were sacrificed, the tumors were stained with cresyl violet or hematoxylin/eosin, their volumes determined by image analysis, and their development followed by magnetic resonance imaging. The mean (+/- SE) tumor volume was 4.4 +/- 1.0 mm3. The injection of liposomes without oxysterol had no effect on tumor growth, whereas injection of liposomes containing 7 beta-hydroxycholesteryl-3-oleate (36 nmol) gave rise to a marked decrease in tumor volume (from 4.4 +/- 1.0 to 0.7 +/- 0.4 mm3). Seven nmol had no effect on tumor growth, 72 nmol were as efficient as 36 nmol, and 144 nmol attenuated the tumor volume by 50% only. Liposomes containing 72 nmol of oleic acid enhanced the tumor volume 4-fold. These findings were confirmed by magnetic resonance imaging. Thus, following induction of tumors in both the right and left sides of the cortex and treatment of the right side, magnetic resonance imaging indicated a significant decrease in tumor volume on the right side only. When C6 cells and 7 beta-hydroxycholesteryl-3-oleate were simultaneously injected, tumors did not develop in 80% of the animals. The clearance of [3H]7 beta-hydroxycholesteryl-3-oleate, of which 75% was converted to cholesterol, reached 99% after 48 h. Other oxysterols did not affect the tumor volume except that 7-keto-cholesteryl-3-oleate decreased the tumor volume by 50%. Thus, the 3-fatty acyl ester and 7 beta-hydroxyl groups are apparently required for the antitumor growth effect. Taken together, these data suggest that 7 beta-hydroxycholesteryl-3-oleate might be useful for local glioblastoma chemotherapy.
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PMID:Local administration of 7 beta-hydroxycholesteryl-3-oleate inhibits growth of experimental rat C6 glioblastoma. 831 91


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