ascorbic-acid and Brain-Neoplasms

For glioblastoma, the treatment with standard of care therapy comprising resection, radiation, and temozolomide results in overall survival of approximately 14-18 months after initial diagnosis. Even though several new therapy approaches are under investigation, it is difficult to achieve life prolongation and/or improvement of patient's quality of life. The aggressiveness and progression of glioblastoma is initially orchestrated by the biological complexity of its genetic phenotype and ability to respond to cancer therapy via changing its molecular patterns, thereby developing resistance. Recent clinical studies of pharmacological ascorbate have demonstrated its safety and potential efficacy in different cancer entities regarding patient's quality of life and prolongation of survival. In this review article, the actual glioblastoma treatment possibilities are summarized, the evidence for pharmacological ascorbate in glioblastoma treatment is examined and questions are posed to identify current gaps of knowledge regarding accessibility of ascorbate to the tumor area. Experiments with glioblastoma cell lines and tumor xenografts have demonstrated that high‑dose ascorbate induces cytotoxicity and oxidative stress largely selectively in malignant cells compared to normal cells suggesting ascorbate as a potential therapeutic agent. Further investigations in larger cohorts and randomized placebo‑controlled trials should be performed to confirm these findings as well as to improve delivery strategies to the brain, through the inherent barriers and ultimately to the malignant cells.

Topics: Animals; Ascorbic Acid; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Glioblastoma; Humans; Infusions, Intravenous; Mice; Oxidative Stress; Permeability; Quality of Life; Tissue Distribution; Treatment Outcome; Xenograft Model Antitumor Assays

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe

Topics: Ascorbic Acid; Basic Helix-Loop-Helix Transcription Factors; Brain Neoplasms; Breast Neoplasms; Carcinogenesis; Dehydroascorbic Acid; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Female; Glioma; Glucose Transport Proteins, Facilitative; Hematologic Neoplasms; Homeostasis; Humans; Hypoxia-Inducible Factor 1; Ketoglutaric Acids; Male; Melanoma; Mixed Function Oxygenases; Neoplasms; Oxidation-Reduction; Polymorphism, Genetic; Prostatic Neoplasms; Proto-Oncogene Proteins; Sodium-Coupled Vitamin C Transporters; Vitamins

The field of quantifying the association between the intake of vitamin C and risk of glioma still has conflicts. Thus, we performed a comprehensive meta-analysis to test the hypothesis that a high intake of vitamin C may be a protective effect on glioma risk.. Pertinent studies were identified by a search in PubMed and Web of Knowledge up to June 2014. The random-effect model was used to combine study-specific results. Publication bias was estimated using Begg' funnel plot and Egger's regression asymmetry test.. Thirteen articles with 15 studies (2 cohort study and 13 case-control studies) involving 3,409 glioma cases about vitamin C intake and glioma risk were used in this meta-analysis. The combined relative risks (RRs) of glioma associated with vitamin C intake was 0.86 (95% CIs = 0.75-0.99). Overall, significant protective associations were also found in the American population (RRs = 0.85, 95% CIs = 0.73-0.98) and case-control studies (RRs = 0.80, 95% CIs = 0.69-0.93). No publication bias was found.. Our analysis indicated that vitamin C intake might decrease the risk of glioma, especially among the Americans.

Topics: Ascorbic Acid; Brain Neoplasms; Diet; Glioma; Humans; Risk

The relationship of vitamins to cancer is very complex. Three types of interactions are possible: the effect of vitamins on tumor growth, the effect of tumors on vitamin metabolism, and the effect of vitamins on chemical carcinogens and anti-tumor chemotherapeutic agents. The significance of vitamins with particular references to vitamins A,B-complex and C, in cancer has been reviewed.

Topics: Antineoplastic Agents; Ascorbic Acid; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Bronchial Neoplasms; Humans; Neoplasms; Nutritional Physiological Phenomena; Tryptophan; Vitamin A; Vitamin B Complex; Vitamin B Deficiency; Vitamins

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemoradiotherapy; Female; Glioblastoma; Humans; Hydrogen Peroxide; Iron; Lung Neoplasms; Male; Mice, Nude; Oxygen; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays

We conducted a single institution phase II trial to evaluate the tolerability and effectiveness of therapy with arsenic trioxide (ATO) and ascorbic acid (AA) with temozolomide (TMZ) in patients with advanced melanoma. Planned enrollment was for 40 patients. Eligible patients were required to have metastatic melanoma with or without brain metastases, an ECOG performance status of 0-2, and adequate organ function. The primary endpoints were overall response rate and degree of grade 4 toxicity. ATO was administered as a loading dose at 0.25 mg/kg/day for 5 days during week 0, and then twice weekly at 0.35 mg/kg during an 8-week cycle. Each infusion of ATO was followed by an infusion of 1000 mg of AA. TMZ was given at the standard dose of 200 mg/m for 5 days during weeks 1 and 5 of each cycle. Eleven patients were enrolled with 10 evaluable for response, five with central nervous system disease. No responses were seen among the first 10 patients and on the basis of a predetermined stopping rule, the trial was terminated. Common grade 1 and 2 side effects included nausea and vomiting (10), fatigue (six), edema (six), rash (six), and elevated AST or ALT (six). Grade 3 and 4 side effects included nausea and vomiting (three), elevated AST or ALT (two), seizure (one), and renal failure (one). This is the first trial combining ATO with chemotherapy in a solid tumor. ATO and AA were administered in the outpatient setting with TMZ in 11 patients with an acceptable side effect profile. No responses were seen in the first 10 evaluable patients leading to early closure of the study. Further studies using ATO and AA with TMZ with this dosing schedule in advanced melanoma are not warranted.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Brain Neoplasms; Dacarbazine; Female; Humans; Male; Melanoma; Middle Aged; Oxides; Skin Neoplasms; Temozolomide

The object of this study was to ascertain the value of topical ascorbic acid in the prevention of radiation dermatitis.. Patients with primary or metastatic brain tumors were eligible. Patients applied a topical solution, twice per day prior to and throughout the course of radiotherapy, to the left and right sides of the head. The radiotherapist and the patient were blinded as to the contents of the solutions. The bottle for one side of the head contained topical ascorbic acid solution. The bottle for the other side of the head contained only vehicle. During and after the course of treatment the radiotherapist scored the skin reaction on both the left and right sides of the irradiated head using a skin reaction scale. The data were analyzed with a matched pair analysis. Since each patient received both treatments (ascorbic acid and control solutions) the statistical analysis concentrated on the paired difference in scores based on the probability of a "preference" for the treatment or control.. Eighty-four patients entered the study. Sixty-five were suitable for analysis. In 10 patients there was a preference for ascorbic acid solution (15%), in 20 patients there was a preference for placebo (31%), and there was a preference for neither in 35 patients (54%). Ascorbic acid solution could be considered to have an effect if the percentage of preferences favoring ascorbic acid over placebo, among those subjects with a preference, significantly exceeded the 50% expected by chance. The observed percentage of preferences for ascorbic acid was only 33% (10 of 30 with a preference; p = .10, two-sided sign test). Patient age, race, sex, and total dose of irradiation had no detectable influence on the comparative skin toxicity scores.. There is no discernible benefit to ascorbic acid lotion, in the manner in which we used it in this trial, for the prevention of radiation dermatitis.

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Brain Neoplasms; Child; Child, Preschool; Double-Blind Method; Female; Humans; Infant; Male; Middle Aged; Prospective Studies; Radiodermatitis; Radiotherapy; Scalp; Solutions

The α thalassemia/mental retardation syndrome X-linked (ATRX) mutation impairs DNA damage repair in glioblastoma (GBM), making these cells more susceptible to treatment, which may contribute to the survival advantage in patients with GBM containing ATRX mutations. To better understand the role of ATRX in GBM, genes correlated with ATRX expression were screened in the Cancer Genome Atlas (702 cases) and Chinese Glioma Genome Atlas (325 cases) databases. Sodium-vitamin C cotransporter 2 (SVCT2) was the most positively correlated gene with ATRX expression. ATRX (about 1.99-fold) and SVCT2 (about 2.25-fold) were upregulated in GBM tissues from 40 patients compared with normal brain tissues from 23 subjects. ShSVCT2 transfection did not alter the in vitro viability of GL261 cells. At the same time, it could inhibit the proliferation of GL261 cells in the orthotopic transplantation model with diminished infiltrating macrophages (CD45

Topics: alpha-Thalassemia; Animals; Ascorbic Acid; Brain Neoplasms; Disease Models, Animal; Glioblastoma; Heterografts; Humans; Macrophages; Mental Retardation, X-Linked; Sodium; Sodium-Coupled Vitamin C Transporters; Symporters; X-linked Nuclear Protein

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a median survival of 14.6 months. GBM is highly resistant to radio- and chemotherapy, and remains without a cure; hence, new treatment strategies are constantly sought. Vitamin C, an essential micronutrient and antioxidant, was initially described as an antitumor molecule; however, several studies have shown that it can promote tumor progression and angiogenesis. Thus, considering the high concentrations of vitamin C present in the brain, our aim was to study the effect of vitamin C deficiency on the progression of GBM using a GBM model generated by the stereotactic injection of human GBM cells (U87-MG or HSVT-C3 cells) in the subventricular zone of guinea pig brain. Initial characterization of U87-MG and HSVT-C3 cells showed that HSVT-C3 are highly proliferative, overexpress p53, and are resistant to ferroptosis. To induce intraperiventricular tumors, animals received control or a vitamin C-deficient diet for 3 weeks, after which histopathological and confocal microscopy analyses were performed. We demonstrated that the vitamin C-deficient condition reduced the glomeruloid vasculature and microglia/macrophage infiltration in U87-MG tumors. Furthermore, tumor size, proliferation, glomeruloid vasculature, microglia/macrophage infiltration, and invasion were reduced in C3 tumors carried by vitamin C-deficient guinea pigs. In conclusion, the effect of the vitamin C deficiency was dependent on the tumor cell used for GBM induction. HSVT-C3 cells, a cell line with stem cell features isolated from a human subventricular GBM, showed higher sensitivity to the deficient condition; however, vitamin C deficiency displayed an antitumor effect in both GBM models analyzed.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Guinea Pigs; Humans; Neoplastic Stem Cells; Xenograft Model Antitumor Assays

Lipid peroxidation represents a marker of secondary brain injury both in traumatic and in non-traumatic conditions-as in major neurosurgical procedures-eventually leading to brain edema amplification and further brain damage. Malondialdehyde (MDA), a lipid peroxidation marker, and ascorbate, a marker of antioxidant status, can represent early indicators of this process within the cerebrospinal fluid (CSF). We hypothesized that changes in cerebral lipid peroxidation can be measured ex vivo following neurosurgery in children.. Thirty-six children (M:F = 19/17, median age 32.9 months; IQR 17.6-74.6) undergoing neurosurgery for brain tumor removal were admitted to the pediatric intensive care unit (PICU) in the postoperative period with an indwelling intraventricular catheter for intracranial pressure monitoring and CSF drainage. Plasma and CSF samples were obtained for serial measurement of MDA, ascorbate, and cytokines.. An early brain-limited increase in lipid peroxidation was measured, with a significant increase from baseline of MDA in CSF (p = 0.007) but not in plasma. In parallel, ascorbate in CSF decreased (p = 0.05). Systemic inflammatory response following brain surgery was evidenced by plasma IL-6/IL-8 increase (p 0.0022 and 0.0106, respectively). No correlation was found between oxidative response and tumor site or histology (according to World Health Organization grading). Similarly, lipid peroxidation was unrelated to the length of surgery (mean 321 ± 73 min), or intraoperative blood loss (mean 20.9 ± 16.8% of preoperative volemia, 44% given hemotransfusions). Median PICU stay was 3.5 days (IQL range 2-5.5 d.), and postoperative ventilation need was 24 h (IQL range 20-61.5 h). The elevation in postoperative MDA in CSF compared with preoperative values correlated significantly with postoperative ventilation need (P = 0.05, r. Our results indicate that lipid peroxidation increases consistently following brain surgery, and it is accompanied by a decrease in antioxidant defences; intraventricular catheterization offers a unique chance of oxidative process monitoring. Further studies are needed to evaluate whether monitoring post-neurosurgical oxidative stress in CSF is of prognostic utility.

Topics: Antioxidants; Ascorbic Acid; Brain Injuries; Brain Neoplasms; Child; Child, Preschool; Cytokines; Drainage; Female; Humans; Infant; Intensive Care Units, Pediatric; Interleukin-6; Interleukin-8; Intracranial Pressure; Lipid Peroxidation; Male; Malondialdehyde; Monitoring, Physiologic; Neurosurgical Procedures; Oxidative Stress; Postoperative Complications; Respiration, Artificial

Constant development of chemotherapeutic strategies has considerably improved the efficiency of tumor treatment. However, adverse effects of chemotherapeutics enforce premature treatment cessation, which leads to the tumor recurrence and accelerated death of oncologic patients. Recently, sodium ascorbate (ASC) has been suggested as a promising drug for the adjunctive chemotherapy of glioblastoma multiforme (GBM) and prostate cancer (PC). To estimate whether ASC can interfere with tumor recurrence between the first and second-line chemotherapy, we analyzed the effect of high ASC doses on the expansion of cells in vitro and in vivo.. Brightfield microscopy-assisted approaches were used to estimate the effect of ASC (1-14 mM) on the morphology and invasiveness of human GBM, rat PC and normal mouse 3T3 cells, whereas cytostatic/pro-apoptotic activity of ASC was estimated with flow cytometry. These assays were complemented by the in vitro CellROX-assisted analyses of intracellular oxidative stress and in vivo estimation of GBM tumor invasion.. ASC considerably decreased the proliferation and motility of GBM and PC cells. This effect was accompanied by intracellular ROS over-production and necrotic death of tumor cells, apparently resulting from their "autoschizis". In vivo studies demonstrated the retardation of GBM tumor growth and invasion in the rats undergone intravenous ASC administration, in the absence of detectable systemic adverse effects of ASC.. Our data support previous notions on anti-tumor activity of high ASC doses. However, autoschizis-related cell responses to ASC indicate that its application in human adjunctive tumor therapy should be considered with caution.

Topics: Animals; Ascorbic Acid; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Glioblastoma; Humans; Male; Mice; Neoplasm Invasiveness; Prostatic Neoplasms; Rats; Reactive Oxygen Species

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor and still lacks effective therapeutic strategies. It has already been shown that old drugs like sulfasalazine (SAS) and valproic acid (VPA) present antitumoral activities in glioma cell lines. SAS has also been associated with a decrease of intracellular glutathione (GSH) levels through a potent inhibition of xc- glutamate/cystine exchanger leading to an antioxidant deprotection. In the same way, VPA was recently identified as a histone deacetylase (HDAT) inhibitor capable of activating tumor suppression genes. As both drugs are widely used in clinical practice and their profile of adverse effects is well known, the aim of our study was to investigate the effects of the combined treatment with SAS and VPA in GBM cell lines. We observed that both drugs were able to reduce cell viability in a dose-dependent manner and the combined treatment potentiated these effects. Combined treatment also increased cell death and inhibited proliferation of GBM cells, while having no effect on human and rat cultured astrocytes. Also, we observed high protein expression of the catalytic subunit of xc- in all the examined GBM cell lines, and treatment with SAS blocked its activity and decreased intracellular GSH levels. Noteworthy, SAS but not VPA was also able to reduce the [

Topics: Amino Acid Transport System y+; Animals; Ascorbic Acid; Brain Neoplasms; Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Drug Therapy, Combination; Glioblastoma; Glutathione; Humans; Intracellular Space; Mesoderm; Neuroglia; Oxidation-Reduction; Rats; Sulfasalazine; Time Factors; Valproic Acid

Topics: Analgesics, Opioid; Ascorbic Acid; Brain Neoplasms; Electron Spin Resonance Spectroscopy; Humans; Mandible; Molar, Third; Tooth Extraction

Glioblastoma (GBM) is one of the lethal central nervous system tumors. One of the widely used chemical agents for the treatment of glioblastoma is temozolomide. It is an orally administered, deoxyribonucleic acid (DNA) alkylating agent. DNA alkylation triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage and thus lower the therapeutic effect of temozolomide. Laboratory and clinical studies indicate that temozolomide"s anticancer effects might be strengthened when combined with other chemotherapeutic agents like etoposide or antioxidant agents like ascorbic acid. In this study, we aimed to evaluate the cytotoxic and oxidative stress effects of ascorbic acid (1000 ?M), temozolomide (100 ?M) and etoposide (25 ?M) agents alone and in dual and triple combinations in a glioblastoma U87 MG cell culture.. The cytotoxic and oxidative stress effects were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) and liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis methods.. Cytotoxicity tests showed that etoposide, temozolomide, "etoposide+ascorbic acid", "temozolomide+ascorbic acid", "temozolomide+etoposide" and "temozolomide+etoposide+ascorbic acid" combinations have anti-proliferative effects. The maximum anti-proliferation response was observed in the "temozolomide+etoposide+ascorbic acid"-added group. Similarly LCMS/ MS analyses showed that minimum oxidative DNA damage occurred in the "temozolomide+etoposide+ascorbic acid"-added group.. Ascorbic acid decreases the cytotoxic and genotoxic effect of etoposide and etoposide-temozolomide combination but it has no meaningful effect on temozolomide"s toxicity.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Dacarbazine; DNA Damage; Drug Synergism; Etoposide; Glioblastoma; Humans; Temozolomide

Polysaccharide extracted from the Maitake mushroom (MP) is considered as a potential anticancer agent. The present study was performed to investigate the cytotoxic effects of MP and vitamin C (VC) alone and in combination on the viability of human neuroglioma M059 K cells in vitro. A combination of MP (1.0 mg/mL) and VC (0.4 mmol/L) led to a 53.10% reduction in cell viability and this treatment induced cell cycle arrest at the G2/M phase, and apoptosis occurred in 38.54% of the cells. Results of Hoechst 33258 staining and Western blot showed apoptotic cells appeared and changes in the expression of apoptosis-related proteins (upregulation of Bax and caspase-3, downregulation of Bcl-2, and activation of poly-(ADP-ribose)-polymerase). Moreover, the activities of caspase-3, caspase-8, and caspase-9 were enhanced in M059 K cells. The inhibiting effect of combined treatment with MP and VC on M059 K cells indicates the mechanism of anticancer activity involved induction of cell apoptosis.

Topics: Apoptosis; Ascorbic Acid; Brain Neoplasms; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Glioma; Grifola; Humans; Polysaccharides

Glioblastoma multiforme is the most malignant tumor of the brain and is challenging to treat due to its highly invasive nature and heterogeneity. Malignant brain tumor displays high metabolic activity which perturbs its redox environment and in turn translates to high oxidative stress. Thus, pushing the oxidative stress level to achieve the maximum tolerable threshold that induces cell death is a potential strategy for cancer therapy. Previously, we have shown that gap junction inhibitor, carbenoxolone (CBX), is capable of enhancing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis in glioma cells. Since CBX is known to induce oxidative stress, we hypothesized that the addition of another potent mediator of oxidative stress, powerful SOD mimic MnTnBuOE-2-PyP(5+) (MnBuOE), could further enhance TRAIL-driven therapeutic efficacy in glioma cells. Our results showed that combining TRAIL + CBX with MnBuOE significantly enhances cell death of glioma cell lines and this enhancement could be further potentiated by CBX pretreatment. MnBuOE-driven cytotoxicity is due to its ability to take advantage of oxidative stress imposed by CBX + TRAIL system, and enhance it in the presence of endogenous reductants, ascorbate and thiol, thereby producing cytotoxic H2O2, and in turn inducing death of glioma cells but not normal astrocytes. Most importantly, combination treatment significantly reduces viability of TRAIL-resistant Asian patient-derived glioma cells, thus demonstrating the potential clinical use of our therapeutic system. It was reported that H2O2 is involved in membrane depolarization-based sensitization of cancer cells toward TRAIL. MnBuOE is entering Clinical Trials as a normal brain radioprotector in glioma patients at Duke University increasing Clinical relevance of our studies.

Topics: Antineoplastic Agents; Apoptosis; Ascorbic Acid; Astrocytes; Biomimetic Materials; Brain Neoplasms; Carbenoxolone; Cell Line; Cell Line, Tumor; Cell Survival; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Gap Junctions; Glioblastoma; Humans; Hydrogen Peroxide; Metalloporphyrins; Organ Specificity; Oxidative Stress; Primary Cell Culture; Sulfhydryl Compounds; Superoxide Dismutase; TNF-Related Apoptosis-Inducing Ligand

Brain tumors are highly aggressive tumors characterized by secretions of high levels of matrix metalloproteinase-2 and -9, leading to tumor growth, invasion and metastasis by digesting the basement membrane and extracellular matrix components. We previously demonstrated the effectiveness of a nutrient mixture (NM) containing ascorbic acid, lysine, proline, and green tea extract in vitro: on activity of urokinase plasminogen activator, matrix metalloproteinases and TIMPs in various human glioblastoma (LN-18, T-98G and A-172) cell lines and on glioblastoma A-172 cell proliferation and Matrigel invasion.. Our main objective in this study was to investigate the effect of the NM in vivo on human glioblastoma U-87 MG cell line.. Athymic male nude mice inoculated with 3·10(6) U-87 MG cells subcutaneously and were fed a regular diet or a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed, the tumors were weighed and measured. The samples were studied histologically.. NM inhibited tumor weight and tumor burden by 53% (p = 0.015) and 48% (p = 0.010), respectively.. These results suggest the therapeutic potential of NM as an adjuvant in the treatment of glioblastoma.

Topics: Animals; Ascorbic Acid; Brain; Brain Neoplasms; Cell Line, Tumor; Dietary Supplements; Glioblastoma; Humans; Lysine; Male; Mice; Mice, Nude; Proline; Tea

Brain tumors are highly aggressive tumors that are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular matrix (ECM) and basement membrane, allowing cancer cells to spread to distal organs. Proteases play a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components. Strong clinical and experimental evidence demonstrates association of elevated levels of urokinase plasminogen activators (uPA) and MMPs with cancer progression, metastasis and shortened patient survival. MMP activities are regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Our main objective was to study the effect of a nutrient mixture (NM) on the activity of uPA, MMPs and TIMPs in various human gliomas. Human glioblastoma (LN-18, T-98G and A-172) cell lines (ATCC) were cultured in their respective media and treated at confluence with NM at 0, 50, 100, 250, 500 and 1000 µg/ml. Analysis of uPA activity was carried out by fibrin zymography, MMPs by gelatinase zymography and TIMPs by reverse zymography. Glioblastoma cell lines LN-18 and T-98G expressed uPA, which was inhibited by NM in a dose-dependent manner. However, no bands corresponding to uPA were detected for the A-172 cell line. On gelatinase zymography, all three cell lines showed bands corresponding to MMP-2 and LN-18 and T-98G showed PMA (100 ng/ml)-induced MMP-9. NM inhibited their expression in a dose-dependent manner. Activity of TIMP-2 was upregulated by NM in all glioma cell lines in a dose-dependent manner. Analysis revealed a positive correlation between uPA and MMP-2 and a negative correlation between uPA/MMPs and TIMP-2. These findings suggest the therapeutic potential of NM in the treatment of gliomas.

Topics: Arginine; Ascorbic Acid; Brain Neoplasms; Camellia sinensis; Cell Line, Tumor; Copper; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Lysine; Manganese; Matrix Metalloproteinases; Micronutrients; Plant Extracts; Proline; Selenium; Tissue Inhibitor of Metalloproteinases; Urokinase-Type Plasminogen Activator

According to our previous study suggesting that antioxidant properties of phytochemicals in the diet decrease glioma aggressiveness, we used a SUVIMAX-like diet ("Supplementation en VItamines et Minéraux AntioXydants") (enriched with alpha-tocopherol, beta carotene, vitamin C, zinc, and sodium selenite), adapted to rats. The present results showed that each of the antioxidants inhibited growth of glioma cells in vitro. When used in combination for in vivo studies, we showed a highly significant delay in the clinical signs of the disease, but not a statistical significant difference in the incidence of glioma in an Ethyl-nitrosourea (ENU)-model. The SUVIMAX-like diet decreased candidate markers of tumoral aggressiveness and gliomagenesis progression. The mRNA expressions of 2 common markers in human glioma: Mn-SOD (Manganese Superoxide Dismutase) and IGFBP5 (insulin growth factor binding protein) were reduced in the tumors of rats fed the antioxidant diet. In addition, the transcripts of two markers linked to brain tumor proliferation, PDGFRb (platelet-derived growth factor receptor beta) and Ki-67, were also significantly decreased. On the whole, our results suggest a protective role for antioxidants to limit aggressiveness and to some extent, progression of gliomas, in a rat model.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; beta Carotene; Brain Neoplasms; Cell Proliferation; Ethylnitrosourea; Female; Glioma; Insulin-Like Growth Factor Binding Protein 5; Ki-67 Antigen; Male; Rats; Receptor, Platelet-Derived Growth Factor beta; RNA, Messenger; Sodium Selenite; Superoxide Dismutase; Zinc

Glioblastomas are lethal brain tumors that resist current cytostatic therapies. Vitamin C may antagonize the effects of reactive oxygen species (ROS) generating therapies; however, it is often used to reduce therapy-related side effects despite its effects on therapy or tumor growth. Because the mechanisms of vitamin C uptake in gliomas are currently unknown, we evaluated the expression of the sodium-vitamin C cotransporter (SVCT) and facilitative hexose transporter (GLUT) families in human glioma cells. In addition, as microglial cells can greatly infiltrate high-grade gliomas (constituting up to 45% of cells in glioblastomas), the effect of TC620 glioma cell interactions with microglial-like HL60 cells on vitamin C uptake (Bystander effect) was determined. Although glioma cells expressed high levels of the SVCT isoform-2 (SVCT2), low functional activity, intracellular localization and the expression of the dominant-negative isoform (dnSVCT2) were observed. The increased glucose metabolic activity of glioma cells was evident by the high 2-Deoxy-d-glucose and dehydroascorbic acid (DHA) uptake rates through the GLUT isoform-1 (GLUT1), the main DHA transporter in glioblastoma. Co-culture of glioma cells and activated microglial-like HL60 cells resulted in extracellular ascorbic acid oxidation and high DHA uptake by glioma cells. This Bystander effect may explain the high antioxidative potential observed in high-grade gliomas. This study strongly suggests that the Bystander effect, that is, glioma cell interaction with oxidant-producing microglia, could be an important mechanism for glioma vitamin C loading in the absence of functional sodium-vitamin C cotransporter 2 (SVCT2) expression. The high cellular vitamin C load in glioma cells results from a high uptake of extracellular dehydroascorbic acid (DHA) generated by neighboring microglia. This Bystander effect may explain the high antioxidative potential observed in high-grade gliomas, considering that high-grade gliomas may be the only neoplasm where oxidant-producing microglia can almost equal the number of tumor cells.

Topics: Antioxidants; Ascorbic Acid; Brain Neoplasms; Bystander Effect; Cell Line, Tumor; Coculture Techniques; Dehydroascorbic Acid; Deoxyglucose; Glioma; Glucose Transporter Type 1; Humans; Microglia; Protein Isoforms; Reactive Oxygen Species; Sodium-Coupled Vitamin C Transporters; Superoxides

Glioblastoma multiforme (GBM) has a very poor prognosis because of its chemo- and radiation therapy resistance. Here we investigated the ability of pharmacological concentrations of ascorbate to radiosensitize primary cells isolated from six GBM patients, mouse astrocytoma cells, and mouse astrocytes. We measured cell viability by trypan blue exclusion, generation of double-stranded DNA breaks by H2AX phosphorylation using fluorescently labeled antibodies and FACS analysis, apoptosis by annexin V/propidium iodide staining, inhibition of autophagy by 3-methyladenine, and cell cycle progression by propidium iodide staining of permeabilized cells. We showed that 5 mM ascorbate in combination with 6 Gy radiation killed more GBM primary cells by generating significantly more double-stranded breaks than either treatment alone (p<0.05). Combined treatment affected viability and double-stranded break generation in normal astrocytes to a much smaller extent. Radiation, but not 5 mM ascorbate, caused G2/M arrest in GBM cells and ascorbate prevented radiation-induced G2/M arrest in combined treatment. Cell death in response to 5 mM ascorbate or combination treatment was not mediated by apoptosis or autophagy. In conclusion, pharmacological concentrations of ascorbate radiosensitize GBM primary cells to a much greater extent than astrocytes; this large therapeutic ratio may be of clinical significance in radiation-resistant cancers.

Topics: Animals; Ascorbic Acid; Brain Neoplasms; Cell Division; Cell Line, Tumor; DNA Damage; Flow Cytometry; G2 Phase; Glioblastoma; Mice; Oxidative Stress; Radiation-Sensitizing Agents

Tumor cells are able to survive and proliferate in spite of their increased oxidative stress. This was taken as a hint for the implication of oxidants/antioxidants in the proliferation of glial-tumor cells. In the present study, an anti-proliferative effect of Naringenin, an antioxidant against cerebrally implanted C6 glioma cells in rats has been investigated. The status of lipid peroxidation/antioxidants, expressions of protein kinase C, nuclear factor κB, cyclin D1, cyclin dependent kinase 4, proliferating cell nuclear antigen, vascular endothelial growth factor, argyophillic nucleolar organizing regions and histopathology of brain tissues of control and experimental rats were analyzed. On supplementation of naringenin (50mg/kg BW for 30 days) to glioma induced rats, there was a reduction in lipid peroxidation with an increased antioxidant status. There was a significant decrease in the expressions of protein kinase C, nuclear factor κB, cyclin D1 and cyclin dependent kinase 4 on naringenin treatment. Further, the drug could modulate the glial-tumor cell proliferation as evidenced from the histopathological findings, argyophillic nucleolar organizing regions staining, proliferating cell nuclear antigen and vascular endothelial growth factor immunostaining. The findings suggest that naringenin could underlie the inhibition of glial tumor cell proliferation in C6 glioma models of rat.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cyclin D1; Cyclin-Dependent Kinase 4; Flavanones; Glioma; Glutathione; Glutathione Peroxidase; Immunohistochemistry; Male; NF-kappa B; Proliferating Cell Nuclear Antigen; Protein Kinase C; Rats; Receptors, Peptide; Thiobarbituric Acid Reactive Substances; Vascular Endothelial Growth Factor A; Vitamin E

Ascorbic acid (AA) is best known for its role as an essential nutrient in humans and other species. As the brain does not synthesize AA, high levels are achieved in this organ by specific uptake mechanisms, which concentrate AA from the bloodstream to the CSF and from the CSF to the intracellular compartment. Two different isoforms of sodium-vitamin C co-transporters (SVCT1 and SVCT2) have been cloned. Both SVCT proteins mediate high affinity Na(+)-dependent L-AA transport and are necessary for the uptake of vitamin C in many tissues. In the adult brain the expression of SVCT2 was observed in the hippocampus and cortical neurons by in situ hybridization; however, there is no data regarding the expression and distribution of this transporter in the fetal brain. The expression of SVCT2 in embryonal mesencephalic neurons has been shown by RT-PCR suggesting an important role for vitamin C in dopaminergic neuronal differentiation. We analyze SVCT2 expression in human and rat developing brain by RT-PCR. Additionally, we study the normal localization of SVCT2 in rat fetal brain by immunohistochemistry and in situ hybridization demonstrating that SVCT2 is highly expressed in the ventricular and subventricular area of the rat brain. SVCT2 expression and function was also confirmed in neurons isolated from brain cortex and cerebellum. The kinetic parameters associated with the transport of AA in cultured neurons and neuroblastoma cell lines were also studied. We demonstrate two different affinity transport components for AA in these cells. Finally, we show the ability of different flavonoids to inhibit AA uptake in normal or immortalized neurons. Our data demonstrates that brain cortex and cerebellar stem cells, neurons and neuroblastoma cells express SVCT2. Dose-dependent inhibition analysis showed that quercetin inhibited AA transport in cortical neurons and Neuro2a cells.

Topics: Animals; Ascorbic Acid; Blotting, Western; Brain Neoplasms; Brain Stem; Cell Line, Tumor; Cerebellum; Cerebral Cortex; DNA, Complementary; Female; Flavonoids; Humans; Immunohistochemistry; In Situ Hybridization; Kinetics; Mice; Neuroblastoma; Neurons; Organic Anion Transporters, Sodium-Dependent; Pregnancy; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sodium-Coupled Vitamin C Transporters; Symporters

Glutathione (GSH) is one of the major antioxidants in the brain. GSH is secreted by astrocytes and this extracellular GSH is used by neurones to maintain and increase their intracellular GSH levels. For efficient GSH trafficking between astrocytes and neurones, GSH needs to be maintained in the reduced form. In model systems, GSH trafficking has been shown to be essential for neuroprotection against a variety of stress conditions. Previously we and others have shown that GSH and thiols are unstable in cell culture media and are easily oxidised. In the present study it is shown that nanomolar concentrations of copper (II) ions can cause decay of GSH in cell culture media. Increased free or redox active copper has been implicated in a variety of diseases and degradation of extracellular GSH is a possible mechanism by which it exerts its harmful effects. Rat astrocytes, a human astrocytoma cell line and astrocyte-conditioned media, in the absence of cells, are able to retard this copper-catalysed decay of GSH and maintain GSH in its reduced form. The protective effect of astrocytes appears to be a combination of copper removing and antioxidant mechanisms. The importance of these protective mechanisms is discussed with regards to neurodegenerative diseases.

Topics: Animals; Ascorbic Acid; Astrocytes; Astrocytoma; Brain Neoplasms; Catalysis; Cell Line, Tumor; Cells, Cultured; Chelating Agents; Copper; Culture Media, Conditioned; Extracellular Space; Fluorescent Dyes; Glutathione; Humans; L-Lactate Dehydrogenase; Male; Pentetic Acid; Phenanthrolines; Rats; Rats, Wistar

A superoxide dismutase (SOD) biosensor for determination of superoxide radicals has been developed by immobilization of superoxide dismutase within gelatin (G) on a Pt electrode surface. The properties of the biosensor have been investigated and optimum conditions-enzyme concentration, glutaraldehyde concentration, and pH-were determined. The response of the G-SOD biosensor was proportional to O2*- concentration and the detection limit was 0.01 mmol L(-1) at a signal-to-noise ratio of 3. The biosensor retained 89% and 60% of its sensitivity after use for three and four weeks, respectively. Immobilization of SOD on gelatin provides a biocompatible microenvironment around the enzyme and stabilizes the activity of the enzyme very efficiently. The superoxide dismutase biosensor was used to determine the antioxidant properties of acetylsalicylic acid-based drugs and the anti-radical activity of healthy and cancerous human brain tissues.

Topics: Ascorbic Acid; Aspirin; Biosensing Techniques; Brain; Brain Neoplasms; Cross-Linking Reagents; Electrochemistry; Equipment Design; Free Radical Scavengers; Humans; Hydrogen-Ion Concentration; Sensitivity and Specificity; Superoxide Dismutase; Superoxides; Time Factors

The aim of the study was to estimate the concentration of glutathione (GSH), ascorbic acid (vitamin C) and thiobarbituric acid (TBA-rs) in single human brain metastases and histologically unchanged nerve tissue. The research was conducted on fragments of neoplasmatic tissue collected from 45 patients undergoing surgery in the Department of Neurosurgery, Medical University of Białystok in years 1996-2002. Concentration of GSH was evaluated using the GSH-400 method, vitamin C using the method of Kyaw and TBA-rs using the method of Salaris and Babs. It has been found that there is a decrease of concentration of GSH and vitamin C and a considerable increase (p < 0.05) of concentration of TBA-rs in investigated single brain human metastasis in correlation to the concentration of the mentioned above substances in unchanged nerve tissue.

Topics: Adult; Aged; Ascorbic Acid; Brain Chemistry; Brain Neoplasms; Female; Glutathione; Humans; Male; Middle Aged; Neoplasm Staging; Thiobarbituric Acid Reactive Substances

The purpose of our research was to assess the activity of GSH-Px, GSSG-R, SOD-1 and concentration of GSH, Vit.C and reactive substances with thiobarbituric acid, in brain tumours with Ist, IInd, IIIrd and IVth levels of biological malignancy. The research was conducted in 105 samples obtained from patients undergoing surgery in the Department of Neurosurgery of the Medical University of Białystok between the years 1996-2001. The obtained values of the above enzyme activities and the concentration of the examined substances in brain tumours were compared to the control values determined in 15 samples of histopathology unchanged nerve tissue.. The increase in all enzymes activities in brain tumours is statistically significant (p < 0.05) as compared to the control level in normal nerve tissue alto a significant decrease (p < 0.05) of the GSH and ascorbate concentration and a significant increase (p < 0.05) in the level of thiobarbituric acid-reactive substances in the examined brain tumours was found in comparison to the concentration of the above substances in normal nerve tissue.

Topics: Ascorbic Acid; Brain Chemistry; Brain Neoplasms; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Humans; Neoplasm Staging; Superoxide Dismutase; Superoxide Dismutase-1

Interactions of the cell adhesion molecules are known to play important roles in mediating inflammation. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), activates the NF-kappaB signaling pathway, which induces the expression of various genes, such as intercellular adhesion molecule-1 (ICAM-1). In this study, the effect of vitamin C on the ICAM-1 expression induced by TNF-alpha in a human neuroblastoma cell line, SK-N-SH was investigated. Treatment with vitamin C resulted in the downregulation of the TNF-alpha-induced surface expression and ICAM-1 mRNA levels in a concentration-dependent manner. Moreover, a gel shift analysis indicated that vitamin C dose-dependently inhibited the NF-kappaB activation and IkappaBalpha degradation induced by TNF-alpha. Taken together, these results suggest that vitamin C downregulates TNF-alpha-induced ICAM-1 expression via the inhibition of NF-kappaB activation.

Topics: Antioxidants; Ascorbic Acid; Biotransformation; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Nucleus; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Humans; Indicators and Reagents; Intercellular Adhesion Molecule-1; Neuroblastoma; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Plasma levels of vitamins A, E and C were analyzed in 102 patients with different types of brain tumors. A follow-up study was done with 27 postoperative patients. On comparison with plasma from normal individuals, vitamin A and E were decreased, but the decrease was statistically insignificant. Vitamin C levels remained in the normal range. In a comparative study of preoperative and postoperative cases, plasma vitamin A levels in postoperative glioma patients were significantly higher than those in the pre-operative state. There was no significant difference in the plasma level of vitamins C and E. The results of the present study suggest that the plasma antioxidant vitamins are not altered effectively in brain tumor cases.

Topics: Adult; Aged; Aged, 80 and over; Ascorbic Acid; Brain Neoplasms; Case-Control Studies; Humans; Middle Aged; Postoperative Period; Vitamin A; Vitamin E

Studies have been demonstrated that vitamin C (ascorbic acid) exhibit the protective role of vin in certain types of cancer. Rat glial tumor cells also have been shown have N-acetyltransferase activity. In this study, we reported the effects of vitamin C on arylamine N-acetyltransferase (NAT) activity and DNA adduct formation in rat glial tumor cell line (C6 glioma). The activity of NAT was measured by high performance liquid chromatography assaying for the amounts of acetylated 2-aminofluorene and p-aminobenzoic acid and nonacetylated 2-aminofluorene and p-amonibenzoic acid. Rat C6 glioma cells were used for examining NAT activity and gene expression and 2-aminofluorene-DNA adduct formation. The results demonstrated that NAT activity and 2-aminofluorene-DNA adduct formation in C6 glioma cells were inhibited and decreased by vitamin C in a dose-dependent manner. But vitamin C did not affect NAT gene expression in examined cells. The apparent kinetic parameters (apparent values of Km and Vmax) from C6 glioma cells were also determined with or without vitamin C cotreatment. The data also indicated that vitamin C decreased the apparent values of Km and Vmax from C6 glioma cells.

Topics: 4-Aminobenzoic Acid; Acetylation; Animals; Arylamine N-Acetyltransferase; Ascorbic Acid; Brain Neoplasms; DNA Adducts; Edetic Acid; Fluorenes; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioma; Kinetics; Rats; Tumor Cells, Cultured

Human glioblastomas (gliomas) are characterized as highly invasive and rapidly growing brain tumors. In this study, we present data on in vitro effect of ascorbyl stearate (Asc-S), a liphophilic derivative of ascorbic acid on cell proliferation, transformation, apoptosis and modulation of expression of insulin-like growth factor-I receptor (IGF-IR) in human glioblastoma multiforme (T98G) cells. Asc-S showed significant inhibition of fetal bovine serum and human recombinant insulin-like growth factor-I (IGF-I) dependent cell proliferation in a dose dependent manner. Treatment of T98G cells with 0, 50, 100 and 150 microM Asc-S for 24h slowed down the cell multiplication cycle with significant accumulation of cells at late S/G2-M phase of cycle. Asc-S treatment (100 microM) reversed the transformed phenotype as determined by clonogenecity in soft agar and also induced apoptosis of T98G. These changes were found to be associated with significant decrease in IGF-IR expression in dose and time dependent manner compared to untreated controls. The data clearly demonstrate that Asc-S has antiproliferative and apoptotic effect on T98G cells probably through modulation of IGF-IR expression and consequent facilitation of programmed cell death.

Topics: Agar; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Survival; Clone Cells; Culture Media; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Immunohistochemistry; In Situ Hybridization; Receptor, IGF Type 1

The aim of the study was to evaluate the concentration of glutathione (GSH), ascorbic acid (Vit C), and thiobarbiturate acid reacting components (MDA) in brain neoplasms in specimens from normal brain tissue. The group of 72 individuals treated surgically for brain neoplasm in Department of Neurosurgery Medical Academy of Białystok (Poland) in the period from 1996 to 1999 was included into the study. The GSH concentration was estimated with GSH-400 method, ascorbic acid by the use of Kyaw method, and MDA by Salaris and Babs method. The statistical analysis revealed diminished concentration of GSH and Vit. C (p < 0.001), and analogous increase of MDA concentration (p < 0.001) in the investigated specimens compared to the mentioned above substances concentration in the specimens obtained from normal brain tissue.

Topics: Adult; Ascorbic Acid; Brain Chemistry; Brain Neoplasms; Colorimetry; Female; Glutathione; Humans; Male; Middle Aged; Thiobarbituric Acid Reactive Substances

The current study determined the extracellular content of glutamate, 10 additional amino acids, lactate, glucose and some antioxidants in a rodent model of malignant glioma, its peritumoral space and the adjacent cortex. RG2 tumors were induced in the right frontal cortex of Fischer-344 rats (n = 10) by a standardized procedure to obtain a maximum sagittal tumor width of 3-4 mm diameter. After confirmation of tumor growth and localization by contrast enhanced MRI three microdialysis probes were implanted simultaneously in the cortex: at the tumor implantation site (tumor), 2 mm caudally, brain around tumor (BAT) and 4 mm caudally (cortex) to the site of implantation. Dialysate concentrations of glutamate were increased 3.9-fold in tumor and 2-fold in BAT compared with cortex. Glycine was elevated 11.4-fold in tumor and 2.6-fold in BAT. Lactate was increased 1.7-fold in tumor, 1.2-fold in BAT. Levels of glucose, ascorbic acid and uric acid were not significantly different in tumor, BAT and cortex. The increased dialysate levels of glutamate and glycine in the peritumoral space may contribute to impaired neuronal function and epileptiform activity associated with this tumor type in humans.

Topics: Amino Acids; Animals; Ascorbic Acid; Brain Chemistry; Brain Neoplasms; Extracellular Space; Female; Glioma; Glucose; Glutamic Acid; Lactic Acid; Magnetic Resonance Imaging; Microdialysis; Rats; Rats, Inbred F344; Uric Acid

Case-control studies of serum antioxidants are difficult to interpret, because antioxidants may be altered by the disease under study. However, because glioblastoma multiforme (GBM) is a relatively rare disease, a cohort study would require a large sample observed for many years. In the present case-control pilot study (34 cases and 35 controls), we evaluated the association between serum levels of ascorbic acid (AA) and alpha- and gamma-tocopherol (alpha-T and gamma-T) measured before diagnostic surgery. To control for influence of GBM on serum AA, alpha-T, and gamma-T, we adjusted for oxidant stress indexes (gamma-glutamyl transpeptidase and uric acid) and an acute-phase response index (serum ferritin). When adjusted, AA is inversely related to GBM (p for trend = 0.007). In addition, AA interacts with alpha-T to further reduce GBM risk (test for interaction, p = 0.04). gamma-T is not associated with GBM (p = 0.71). However, gamma-glutamyl transpeptidase (p = 0.004), coenzyme Q (p = 0.01), and ferritin (p = 0.009) are positively and uric acid (p = 0.000) is negatively related to GBM. We conclude that 1) AA and alpha-T are jointly related to GBM after adjustment for GBM-produced oxidant stress and 2) there is a strong association between the presence of GBM and oxidant stress.

Topics: Acute-Phase Reaction; Aged; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Brain Neoplasms; Case-Control Studies; Female; Ferritins; gamma-Glutamyltransferase; gamma-Tocopherol; Glioblastoma; Humans; Male; Middle Aged; Oxidative Stress; Pilot Projects; Risk Factors; Ubiquinone; Uric Acid

The biosynthesis of type VI collagen was studied in human glioblastoma cell line, U-87 MG. The effects of ascorbic acid on type VI collagen synthesis and secretion were investigated. After ascorbic acid treatment, type VI collagen in cell layers increased from 4.48% in control to 6.63% in the ascorbic acid treated cultures, an increase of 48%. The effect of ascorbic acid on type VI collagen synthesized by glioblastoma cells was lower than that reported for osteosarcoma cells (Engvall et al., 1986). The reason for these differences is still under investigation. The function of type VI collagen in glioblastoma cells is still unknown. We utilized the collagen gel system to elucidate the possible roles of type VI collagen in glioblastoma cells in vitro. Glioblastoma cells in collagen gels showed a stellate shape with long, branched processes in all directions. The strong positive reactivity of type VI collagen detected on cell bodies and cell processes by anti-type VI collagen antibody indicated that this specific collagen was associated with cell surfaces and processes, without releasing or diffusing into the gels. Type VI collagen was directly involved in the cell process extension. When living cells were treated with anti-type VI collagen antibody, a variation of cell morphology was observed. Instead of a stellate shape with processes, cells formed clusters without or with very short processes. These data suggest that type VI collagen, synthesized and secreted by glioblastoma cells, may play a role in tumor cell adhesion and spreading, and enhance cell process extension, penetration, and invasion into collagen gels.

Topics: Antibodies; Artificial Organs; Ascorbic Acid; Bone Neoplasms; Brain Neoplasms; Cell Adhesion; Cell Membrane; Cell Shape; Cell Surface Extensions; Collagen Type VI; Extracellular Matrix; Gels; Glioblastoma; Humans; Models, Biological; Neoplasm Invasiveness; Osteosarcoma; Up-Regulation

The aim of the present study was to investigate the oxidative status in astrocytoma. Samples of brain tissue from the centre to the periphery of the tumor were obtained from 11 astrocytoma patients undergoing computer tomography-guided stereotaxic operation, who had been previously treated with the corticosteroid dexamethasone. Part of the sample was investigated histologically for clarification of tumor type, and the presence of neoplastic and non-neoplastic tissue and necrosis. The rest was used for the quantification of the antioxidants ascorbic acid, uric acid, glutathione and cysteine by high performance liquid chromatography, and for quantification of DNA. Levels of antioxidants were calculated as micrograms/g fresh tissue and mumol/g DNA, a parameter related to cell content. There was significantly more DNA in neoplastic samples than in non-neoplastic ones, indicating increased cell density. Uric acid (micrograms/g fresh tissue) was significantly increased in neoplastic compared with non-neoplastic tissue, and levels were even higher in necrotic tissue. There were no significant differences between neoplastic and non-neoplastic tissue levels of ascorbic acid, glutathione or cysteine, expressed as micrograms/g fresh tissue. However, when levels of these three compounds were expressed as mumol/g DNA, i.e. taking into account the higher cell density, ascorbic acid, glutathione and cysteine were significantly reduced in neoplastic samples compared with non-neoplastic ones. Results thus show that there are differences between the antioxidant levels in astrocytoma and non-neoplastic tissue, providing additional support for the hypothesis that free radicals play a role in tumor growth.

Topics: Adult; Aged; Antioxidants; Artifacts; Ascorbic Acid; Astrocytoma; Biopsy; Brain Chemistry; Brain Edema; Brain Neoplasms; Combined Modality Therapy; Cysteine; Dexamethasone; DNA, Neoplasm; Female; Free Radicals; Glioblastoma; Glutathione; Humans; Male; Middle Aged; Necrosis; Neoplasm Proteins; Oxidation-Reduction; Oxidative Stress; Phenytoin; Solubility; Stereotaxic Techniques; Tomography, X-Ray Computed; Uric Acid; Water

The interactions of nitric oxide (NO) and ascorbate were explored on the control of growth of human brain tumor cells. Sodium nitroprusside, a NO-generating agent, inhibited the growth of SK-N-MC human neuroblastoma cells in a dose-dependent manner. The growth inhibitory effect of nitroprusside was potentiated by sodium ascorbate and inhibited by hemoglobin. Ascorbate-induced potentiation was also observed in U-373 MG human astrocytoma cells. In both tumor cell lines, this potentiation was blocked by catalase, suggesting that hydrogen peroxide may be involved in the potentiation mechanism. In astrocytoma cells, mannitol or deferoxamine also reversed ascorbate-induced potentiation, indicating involvement of hydroxyl radical. These results suggest that the combined treatment with nitroprusside and ascorbate may be a valuable therapeutic strategy for brain tumors.

Topics: Ascorbic Acid; Brain Neoplasms; Drug Synergism; Free Radicals; Growth Inhibitors; Humans; In Vitro Techniques; Nitroprusside; Tumor Cells, Cultured

Levodopa, at concentrations of 0.25 x 10(-4) M or larger, is toxic for the human neuroblastoma cell NB69. Toxicity is associated with high levels of quinones, increased activity of complex II-III, and lack of changes of complex I of the mitochondrial respiratory chain. Deprenyl, which does not alter the production of quinones, has a partial protective effect. Tocopherol, 23 or 115 x 10(-6) M, lacks significant preventive effect on levodopa toxicity, but ascorbic acid, 10(-3) M, prevents levodopa toxicity and quinone formation. Deprenyl, 10(-4) M, provides additional protection in cultures treated with levodopa and ascorbic acid. Our results indicate that ascorbic acid and deprenyl prevent levodopa neurotoxicity by unrelated mechanisms. Both compounds should be considered as complementary drugs to test for slowing the progression of Parkinson's disease.

Topics: Ascorbic Acid; Brain; Brain Neoplasms; Catecholamines; Cell Line; Drug Interactions; Female; Humans; Levodopa; Male; Neuroblastoma; Parkinson Disease; Quinones; Selegiline

The authors present their results regarding the use of a buffered solution of glycerol 30%-sodium ascorbate 20% (GLIAS) for the treatment of brain oedema and intracranial hypertension. GLIAS was perfused intravenously in 80 patients with several types of brain oedema. In every patients serum and urinary osmolarity, diuresis, main blood and urine parameters, and ICP were monitored. Following GLIAS infusion an increase in plasma osmolarity was observed, changing the average basal value plus 13.4% after 15 min., 10.5% after 30'. At the same time there was a reduction of ICP and improvement in cerebral compliance. In each case there was a decrease in intracranial hypertension and brain oedema without significant collateral effects.

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Brain Edema; Brain Injuries; Brain Neoplasms; Buffers; Cerebral Hemorrhage; Child; Dose-Response Relationship, Drug; Female; Glycerol; Humans; Hypertonic Solutions; Infusions, Intravenous; Intracranial Aneurysm; Intracranial Pressure; Male; Middle Aged; Postoperative Complications; Pseudotumor Cerebri

The ESR spectrum, attributed to the ascorbic acid (ascorbyl) radical and obtained by exposing freeze dried material to air, can not be used as proof for the occurrence of in vivo free radical reactions. Depending on the method of freeze drying, the content of blood or hemolyzed blood is the dominant factor in creating higher than normal ESR signals in brain or related tissue. These findings explain why the signal, though larger in many human brain tumours than in their surroundings, is not indicative of malignancy. No differences are seen between oedematous and normal tissue. The ascorbyl radical is definitely not stable in aqueous solution, which indicates that fresh tissue sections can also not be used to study in vivo radicals by ESR.

Topics: Animals; Ascorbic Acid; Brain; Brain Neoplasms; Electron Spin Resonance Spectroscopy; Freeze Drying; Hemolysis; Humans; Oxygen; Rats; Rats, Inbred Strains

The uptake of 99mTc-pertechnetate (TcO4), 99mTc-iron-ascorbic acid (Feasc), 99mTc-Solcocitran (Solcocitran), 99mTc-diphosphonate (HEDP) and 67Ga-citrate (Ga) in various brain lesions was compared. Influence of time from injection was also studied on the first three compounds. A rank correlation method was used to compare the scans which were judged visually by three independent observers. There was good agreement between the observers, as measured by Kendall's tau, but the concordance between rankings within the same type of lesion, as measured by Kendall's W, was rather poor. There was no significant difference in the uptake of TcO4, Feasc and Solcocitran. Ga showed generally poor uptake and its uptake in tumours and infarcts did not differ significantly. However, when HEDP and TcO4 were compared in two groups (I: Infarcts, haemorrhages and bone invading meningiomas, and II: Tumours not invaded into bone) a highly significant difference was obtained with much higher uptake of HEDP in Group I.

Topics: Adult; Ascorbic Acid; Brain Diseases; Brain Neoplasms; Cerebral Hemorrhage; Cerebral Infarction; Citrates; Diphosphonates; Gallium Radioisotopes; Humans; Organotechnetium Compounds; Radionuclide Imaging; Sodium Pertechnetate Tc 99m; Technetium; Technetium Compounds

A mixture of vitamins C and B12 in high dosage, which has been reported to eradicate ascites tumors in rats, was tested for its antineoplastic effect against the L9 glioma in Fisher CDF strain rats. No difference in survival time between animals receiving the vitamin mixture and controls could be demonstrated. Possible reasons for the different response to therapy in the two experimental tumor systems are discussed.

Topics: Animals; Ascorbic Acid; Brain Neoplasms; Drug Evaluation, Preclinical; Drug Therapy, Combination; Glioma; Male; Neoplasm Transplantation; Neoplasms, Experimental; Orthomolecular Therapy; Rats; Vitamin B 12

Sixteen radiopharmaceuticals for brain tumor localization have been compared in a mouse brain tumor model. A rating system is presented for such intercomparison. The rusults indicate that 111-in-chloride injected at pH 1.5 has the most favorable biologic characterisTICS FOR BRAIN TUMOR IMAGING.

Topics: Animals; Ascorbic Acid; Bleomycin; Brain Neoplasms; Chlormerodrin; Gallium; Indium; Iron; Mercury Isotopes; Methylcholanthrene; Mice; Neoplasm Transplantation; Pentetic Acid; Radioisotopes; Radionuclide Imaging; Sarcoma, Experimental; Serum Albumin, Radio-Iodinated; Technetium; Tin; Ytterbium

To assess their carcinogenic effects, the ethylnitrosourea (ENU) precursors, ethylurea and sodium nitrite, [were administered to pregnant hamsters as a single intragastic] dose on day 15 of gestation, or introduced into the cecum on day 14. Since sodium ascorbate (NaASC) inhibits the biosynthesis of nitrosamides, identical doses of the precursors were given concomitantly with NaASC. Progeny of mothers treater intragastrically developed significant incidences of neurogenic tumors of the peripheral nervous system, with a predominance in females. The concurrent administration of NaASC with ENU precursors prevented carcinogenic effects in the progency, whereas the simultaneous inoculation of the precursors into the cecum produced no carcinogenic effects in the offspring.

Topics: Animals; Ascorbic Acid; Astrocytoma; Brain Neoplasms; Cecum; Cricetinae; Ethylnitrosourea; Female; Intubation, Gastrointestinal; Male; Maternal-Fetal Exchange; Neoplasms, Experimental; Nitrites; Nitroso Compounds; Peripheral Nervous System Neoplasms; Pons; Pregnancy; Sex Factors; Urea

Topics: Adolescent; Adult; Ascorbic Acid; Brain Neoplasms; Cerebrospinal Fluid; Child; Child, Preschool; Humans; Infant; Middle Aged

Topics: Animals; Ascorbic Acid; Brain Neoplasms; Carcinogens; Cranial Nerves; Drug Interactions; Female; Gestational Age; Nitrites; Peripheral Nervous System Neoplasms; Pregnancy; Rats; Spinal Cord Neoplasms; Urea

Topics: Animals; Ascorbic Acid; Brain Chemistry; Brain Neoplasms; Iron; Kidney; Liver; Methylcholanthrene; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Pentetic Acid; Radionuclide Imaging; Sarcoma, Experimental; Technetium; Time Factors; Tin

Topics: Amyotrophic Lateral Sclerosis; Ascorbic Acid; Brain Neoplasms; Cerebrospinal Fluid Proteins; Cerebrovascular Disorders; Humans; Methods; Nucleic Acids; Spectrophotometry; Ultraviolet Rays

Topics: Adult; Ascorbic Acid; Brain Neoplasms; Child; Female; Humans; Iodine Radioisotopes; Iron; Male; Medulloblastoma; Middle Aged; Neoplasm Metastasis; Radiometry; Radionuclide Imaging; Sarcoma, Synovial; Technetium

Topics: 17-Hydroxycorticosteroids; Adolescent; Adrenal Cortex Hormones; Adrenal Gland Diseases; Adrenocorticotropic Hormone; Adult; Aged; Ascorbic Acid; Brain Diseases; Brain Neoplasms; Female; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Pituitary Diseases; Thyroid Diseases; Urine