dinoprost and parinaric-acid

Intraesophageal administration of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction radiation has been shown to protect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fractionated radiation in two protocols: (i) 18 Gy daily for four days with MnSOD-PL administration 24 hr prior to the first and third fraction, or (ii) 12 Gy daily for six days with MnSOD-PL 24 hr prior to the first, third, and fifth fraction. Control radiated mice received either no liposomes only or LacZ (bacterial beta-galactosidase gene)-plasmid/liposome (LacZ-PL) by the same schedules. We measured thiol depletion and lipid peroxidation (LP) in whole esophagus and tested the effectiveness of a new plasmid, hemagglutinin (HA) epitope-tagged MnSOD (HA-MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 microl of plasmid/liposomes containing 200 microg of plasmid DNA), showed a significant reduction in morbidity, decreased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increase in peroxidized lipids and reduction in overall antioxidant levels, reduced thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in the basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidase-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration significantly improved tolerance to fractionated radiation and modulated radiation effects on levels of GSH and lipid peroxidation (LP). These studies provide further support for translation of MnSOD-PL treatment into human esophageal radiation protection.

Topics: Animals; Biomarkers; Cells, Cultured; Chromatography, High Pressure Liquid; Dinoprost; Dose-Response Relationship, Drug; Epitopes; Esophagitis; Fatty Acids, Unsaturated; Female; Hemagglutinins; Lac Operon; Lipid Metabolism; Lipid Peroxidation; Liposomes; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Plasmids; Radiotherapy; Superoxide Dismutase; Time Factors

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