dinoprost and Brain-Neoplasms

This study compares the effect of gamma-linolenic acid (GLA) and its precursor linoleic acid (LA) on survival of 36B10 malignant rat astrocytoma cells and 'normal' rat astrocytes. GLA was cytotoxic to 36B10 cells but not to astrocytes. By contrast, LA supplementation did not affect the survival of either cell types. There were minor differences in the uptake, distribution and use of radiolabelled GLA and LA by the 36B10 cells and astrocytes. GLA and LA supplementation increased the total polyunsaturated fatty acid (PUFA) content of the cells indicating increased oxidative potential. However, elevated levels of 8-isoprostane, an indicator of increased oxidative stress, were only observed in the GLA supplemented 36B10 cells. Addition of the antioxidant trolox to GLA-enriched 36B10 cells blocked the cytotoxic effect. Further, GLA enhanced the radiation sensitivity of the astrocytoma cells but not the astrocytes; trolox blocked the GLA-mediated increase in astrocytoma cell radiosensitivity. LA did not affect the radiation response of either cell type. While cyclo-oxygenase inhibitors did not affect GLA cytotoxicity, they blocked the enhanced radiation response of GLA-supplemented cells. The lipoxygenase inhibitor NDGA did not affect the toxicity produced by GLA. Thus, GLA is toxic to the neoplastic astrocytoma cells but not to normal astrocytes.

Topics: alpha-Linolenic Acid; Animals; Antineoplastic Agents; Antioxidants; Astrocytes; Astrocytoma; Brain Neoplasms; Cell Death; Chromans; Cyclooxygenase Inhibitors; Dinoprost; F2-Isoprostanes; gamma-Linolenic Acid; Ibuprofen; Indomethacin; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured; Vitamin E

The cytotoxic effects of cis-parinaric acid, a plant-derived 18-carbon polyunsaturated fatty acid, were assessed in vitro on normal and neoplastic glia. After being incubated for 24 hours in the presence of 12 mumol/L cis-parinaric acid, 36B10 glioma cultures demonstrated nearly 90% toxicity (unpaired Student's t test, P < 0.001). Similar results were obtained after the exposure of C6 rat glioma cultures, A172 human glioma cultures, and U-937 human monocytic leukemia cultures to cis-parinaric acid. In contrast, fetal rat astrocytes incubated with 12 mumol/L cis-parinaric acid demonstrated no significant toxicity (3% reduction, P = 0.12); fetal rat astrocytes showed only 20% toxicity after exposure to 40 mumol/L cis-parinaric acid (P = 0.001). The cytotoxic effects of cis-parinaric acid were antagonized with the addition of equimolar concentrations of alpha-tocopherol. Enzyme immunoassay of treated 36B10 glioma supernatant fluid for 8-isoprostane (a known oxidative metabolite) demonstrated a 10-fold increase of 8-isoprostane over 24 hours (123.0 +/- 10.3 versus 10.0 +/- 0.7 pg/ml for control, P < 0.001). These studies indicate that cis-parinaric acid may be significantly cytotoxic to malignant glioma cells in concentrations that spare normal astrocytes and that the mechanism of cytotoxicity is related to an oxidative process. The selective cytotoxic effect of cis-parinaric acid we describe represents the first step in the development of new chemotherapeutic agents for gliomas; these new agents act by preferentially enhancing lipid peroxidation in neoplastic cells.

Topics: Animals; Antineoplastic Agents; Arachidonic Acids; Astrocytes; Brain Neoplasms; Cell Line; Cell Survival; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Fatty Acids, Unsaturated; Glioma; Humans; Lipid Peroxidation; Rats; Tumor Cells, Cultured

Brain tumours produce prostaglandins in vitro; their in vivo production has been studied by determining the levels of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha and thromboxane B2 in tumour cyst fluid and ventricular CSF taken from 21 patients with a variety of intracranial tumours. The levels were high in tumour cyst fluid but there was no overall increase in ventricular CSF. Hence, brain tumours do not produce a consistent pattern of abnormality of eicosanoid concentrations in the ventricular CSF that would be useful for diagnosis. If brain tumours produce excess quantities of these prostaglandins in vivo as they do in vitro, these prostaglandins may be rapidly cleared by the cerebral microvasculature unless compartmentalized within a tumour cyst.

Topics: 6-Ketoprostaglandin F1 alpha; Body Fluid Compartments; Body Fluids; Brain Edema; Brain Neoplasms; Dinoprost; Dinoprostone; Eicosanoids; Female; Humans; Hydrocephalus; Intervertebral Disc Displacement; Male; Thromboxane B2

Tumour cell-rich platelet-free preparations were isolated from 21 fresh samples of human intracranial tumours using enzymic digestion, followed by discontinuous density gradient centrifugation on Percoll and (14 preparations) adherence on plastic. Of the disaggregated cells 79.8 to 97.7% (mean 86.2%) were tumour cells, and mean cell viability was 82.6%. All the tumours produced prostaglandin (PG), E2, F2 alpha, 6 oxo F1 alpha and Thromboxane B2 during 16 hours of incubation but the amount varied widely. Highest production of PGE2 and TXB2 per 10(5) cells was by the eight meningiomas in which the prostanoid profile closely resembled that of circulating monocytes.

Topics: 6-Ketoprostaglandin F1 alpha; Astrocytoma; Brain Neoplasms; Dinoprost; Dinoprostone; Glioblastoma; Glioma; Humans; Meningeal Neoplasms; Meningioma; Monocytes; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes