prostaglandin-d2 and Brain-Neoplasms

Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9:1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1 ± 4.8% and 97.6 ± 16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3-21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.

Topics: Amides; Animals; Brain Neoplasms; Cell Line, Tumor; Fluorine Radioisotopes; Gene Expression Regulation, Neoplastic; Glutathione; Intramolecular Oxidoreductases; Lipocalins; Male; Positron-Emission Tomography; Prostaglandin D2; Prostaglandin H2; Radioactive Tracers; Radiochemistry; Rats; Rats, Sprague-Dawley

15-Deoxy-(Delta12,14)-prostaglandin J(2) (15d-PGJ(2)) is a naturally occurring cyclopentenone metabolite of prostaglandin D(2) (PGD(2)) and is known as a specific potent ligand for the peroxisome proliferators activator receptor-gamma (PPARgamma). 15d-PGJ(2) inhibits cell growth and induces apoptosis in a number of different cancer cells. However, the underlying mechanism by which 15d-PGJ(2) induces cell death remains to be defined. The present study was undertaken to determine the effect of 15d-PGJ(2) on cell death in A172 human glioma cells. 15d-PGJ(2) caused reactive oxygen species (ROS) generation. 15d-PGJ(2)-induced ROS production and cell death were prevented by the antioxidant N-acetylcysteine. Activation of mitogen-activated protein kinases (MAPK) was not observed in cells treated with 15d-PGJ(2 )and inhibitors of MAPK subfamilies also were not effective in preventing 15d-PGJ(2)-induced cell death. 15d-PGJ(2) treatment caused mitochondrial dysfunction, as evidenced by depolarization of mitochondrial membrane potential. 15d-PGJ(2) induced caspase activation at 24 h of treatment, but the 15d-PGJ(2)-induced cell death was not prevented by caspase inhibitors. The antiapoptotic protein XIAP levels and release of apoptosis inducing factor (AIF) into the cytosol were not altered by 15d-PGJ(2) treatment. Taken together, these findings indicate that 15d-PGJ(2) triggers cell death through a caspase-independent mechanism and ROS production and disruption of mitochondrial membrane potential play an important role in the 15d-PGJ(2)-induced cell death in A172 human glioma cells.

Topics: Brain Neoplasms; Caspases; Cell Death; Cell Line, Tumor; Glioma; Humans; Mitogen-Activated Protein Kinases; Prostaglandin D2; Reactive Oxygen Species

Cell kinetics of cancers have been described in books, texts and other reports, but the correlation with action mechanism of antineoplastic agents has rarely been mentioned in the literature. The action mechanism of the antineoplastic agents such as interferon, ACNU and cisplatin was analyzed with use of propidium iodide and BrdU double staining by flow cytometer. Interferon showed S phase accumulation, ACNU and cisplatin blocked the stage of G(2)M phase. Flow cytometry was useful for the analysis of cell kinetics.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Cycle; Cisplatin; Flow Cytometry; Glioma; Humans; Interferons; Nimustine; Prostaglandin D2; Tumor Cells, Cultured

The prostaglandins (PG) are known to have various physiological effects. Some series of prostaglandins such as PG D2 have been reported to inhibit growth of tumor cells. In this study, the growth-inhibitory effects of PG A2, PG D2, PG J2 and 6-keto PGE1 were investigated in nude mice receiving subcutaneous transplant of human brain tumor. One to two milligram of prostaglandins was given intraperitoneally every day for three weeks. Tumor volumes were measured twice weekly and the tumor reduction rates (treated/control) were evaluated. T/C rate treated with PG D2 or PG A2 was 50-60% respectively. The effectiveness of PG J2 or 6-keto PGE1 was inferior to that of PG A2 or PG D2. But in the evaluation of antitumor effects of PG J2, we must consider the fact that the activity of PG J2, is liable to be lost. The effect of PG D2 on proliferation of cultured glioma cells was also studied. At concentrations of 10 micrograms/ml, PG D2 strongly inhibited the proliferation of glioma cells. However, precise mechanism of prostaglandin action is presently unknown. Further studies are required to clarify the mechanism of antitumor effects of prostaglandins.

Topics: Alprostadil; Animals; Brain Neoplasms; Drug Screening Assays, Antitumor; Glioma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Prostaglandin D2; Prostaglandins; Prostaglandins A; Tumor Cells, Cultured

Prostaglandin (PG) D2 was examined for its effect on the growth of a mouse brain tumor cell line in vitro and in vivo. In this study, we used 203 glioma which had been originally induced by methylcholanthrene in C57BL mice and proved to be subcutaneously transplantable and also maintainable in a cell culture system in vitro. Marked inhibition of cell growth was observed in a PGD2-treated group in vitro at a concentration of 5 micrograms/ml. In the in vivo experiment, intraperitoneal or intratumoral administration of PGD2 (0.5 mg/kg) every day for four weeks was started after subcutaneous transplantation. In a control group, the same amount of ethanol without PGD2 was administered. Inhibition of tumor growth was seen with intratumoral administration, although no inhibition was seen with intraperitoneal administration. Histological examination revealed no remarkable change after PGD2 administration. However, on the DNA histogram, an increment of the G0G1 phase and a decrement of the G2M phase occurred after intratumoral administration of PGD2. It was suggested that local administration of PGD2 might be effective through the inhibition of DNA synthesis.

Topics: Animals; Brain Neoplasms; Cell Division; Cell Line; Cells, Cultured; DNA, Neoplasm; Glioma; Interphase; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Prostaglandin D2; Prostaglandins D