gamma-linolenic-acid and Astrocytoma

Intracranial infusions of gamma-linolenic acid (GLA), an essential fatty acid, have been used as an adjuvant therapy following malignant glioma resection; however, little is known about the dose response of glioma cells to this therapy. In this in vitro study the authors address this important pharmacological question.. Glioma spheroids derived from U87, U373, MOG-G-CCM, and C6 cell lines were grown in collagen gel and exposed to a range of GLA concentrations (0-1 mM) for 5 days. The diameter of glioma spheroids was measured, the apoptotic index was assessed using both the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and cell morphological testing, and the levels of proliferating cell nuclear antigen were also measured.. The dose-response patterns were similar for all four glioma spheroids. Low concentrations of GLA (<100 microM) increased both apoptosis and proliferation with a net increase in tumor growth and invasion, whereas high-dose GLA (>100 microM) significantly impaired spheroid cell growth. The proliferative effects of low-dose GLA could be a hazard in the clinical treatment of malignant glioma; however, because of the low toxicity of GLA against normal cells, local delivery of millimolar doses of GLA could significantly reduce tumor size.

Topics: Animals; Apoptosis; Astrocytoma; Brain Neoplasms; Cell Division; Dose-Response Relationship, Drug; gamma-Linolenic Acid; Glioblastoma; Humans; Neoplasm Invasiveness; Spheroids, Cellular; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Astrocytes; Astrocytoma; Cell Survival; Cyclooxygenase Inhibitors; Dinoprost; F2-Isoprostanes; Fatty Acids; gamma-Linolenic Acid; Glioma; Ibuprofen; Lipoxygenase Inhibitors; Oxidative Stress; Radiation Tolerance; Rats; Tumor Cells, Cultured

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

Polyunsaturated fatty acids (PUFA) such as gamma-linolenic acid (GLA, 18:3n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) have been shown to be cytotoxic to tumor cells. The objective of this work was to study the effects of PUFA on the radiation response of a 36B10 rat astrocytoma cell line. Supplementation of the astrocytoma cells with 15-45 microM GLA, EPA, or DHA produced marked changes in the fatty acid profiles of their phospholipids and neutral lipids. The methylene bridge index of these lipids increased significantly. These PUFA also exerted cytotoxic effects, as determined using the clonogenic cell survival assay. While GLA and DHA produced a moderate cell-killing effect, EPA was extremely cytotoxic, especially at a concentration of 45 microM. The monounsaturated oleic acid (OA, 18:1n-9) did not affect cell survival. Further, all three PUFA, and particularly GLA, increased the radiation-induced cell kill; OA did not enhance the effect of radiation. alpha-Tocopherol acetate blocked the enhanced radiation sensitivity of GLA- and DHA-supplemented cells. In conclusion, GLA, EPA, and DHA supplementation prior to, during, and after irradiation can enhance the radiation-induced cytotoxicity of rat astrocytoma cells. GLA and DHA supplementation post-irradiation also enhanced the radiation response of the 36B10 cells. Because GLA maximally increases the radioresponsiveness of a rat astrocytoma, this PUFA might prove useful in increasing the therapeutic efficacy of radiation in the treatment of certain gliomas.

Topics: alpha-Tocopherol; Animals; Astrocytoma; Cell Survival; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Lipid Metabolism; Oleic Acid; Phospholipids; Radiation-Sensitizing Agents; Rats; Time Factors; Tocopherols; Tumor Cells, Cultured; Vitamin E

gamma-Linolenic acid (GLA) has been shown to have selective tumoricidal action both in vitro and in vivo. Earlier, in a limited clinical study, we have demonstrated that intra-tumoral administration of GLA can induce regression of human gliomas. In an extension of this study, we evaluated the effect of intra-cerebral injection of GLA on normal dog brain and in 15 patients with malignant gliomas. Histopathological examination revealed that GLA is not cytotoxic to the normal dog brain cells. Administration of 10 mg of GLA via a cerebral reservoir placed in the tumour bed, at the rate of 1 mg/day over a period of 10 days, revealed that GLA is not only safe and non-toxic but can also regress cerebral gliomas as evaluated by computerised tomography and increased survival of the patients by 1.5-2 years. Based on these results and our earlier in vitro study, we suggest that GLA is a safe anti-tumour agent and recommend its use in the management of human gliomas.

Topics: Adult; Aged; Aged, 80 and over; Animals; Astrocytoma; Brain Neoplasms; Dogs; Female; gamma-Linolenic Acid; Glioblastoma; Glioma; Humans; Injections, Intralesional; Male; Middle Aged; Tomography, X-Ray Computed