Capillary permeability factor secreted by malignant brain tumor. Role in peritumoral brain edema and possible mechanism for anti-edema effect of glucocorticoids.
Conditioned media from two human malignant gliomas, C6 rat glioma, Walker 256 carcinosarcoma, and normal human glia were concentrated 50-fold to create a culture supernatant (SUP-C). The effect of SUP-C on rat brain capillary permeability was investigated by measuring the entry of 14C-aminoisobutyric acid (14C-AIB) by means of quantitative autoradiography. The SUP-C contained proteins with a molecular weight of 10 kD or greater. The SUP-C from all tumor cells markedly increased brain capillary permeability, indicating the presence of a permeability factor, whereas that from normal glial cells did not. Glioma cells produced more factor after incubation for 20 hours than 4 hours. The activity of capillary permeability factor in the SUP-C was inhibited by pretreatment of animals with BW755C (lipoxygenase inhibitor), but not with indomethacin (cyclo-oxygenase inhibitor). Pretreatment of animals with dexamethasone prior to intracerebral infusion of tumor SUP-C significantly reduced the factor-induced increase in capillary permeability. On the other hand, coincubating glioma cells with dexamethasone produced SUP-C with a permeability activity that was about one and a half times greater than that without dexamethasone. These results indicate that glucocorticoids produce their anti-edema effects by directly acting on capillary endothelial cells, possibly through the inhibition of phospholipase A2 activity, resulting in a decrease of lipoxygenase rather than cyclo-oxygenase products. The production of capillary permeability factor by tumor cells was not inhibited, but rather enhanced, by administration of glucocorticoids.
Ohnishi
T
T
George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Sher
P B
PB
Posner
J B
JB
Shapiro
W R
WR
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000627:therapeutic use; D000818:Animals; D001345:Autoradiography; D001929:Brain Edema / Q000188:drug therapy / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D002296:Carcinosarcoma / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003907:Dexamethasone; D007213:Indomethacin