[In vitro and in vivo immunobiological responses of glioblastoma to human natural tumor necrosis factor-alpha].
Biological effects of human natural tumor necrosis factor-alpha (TNF) on glioblastoma cells in vitro and on glioma patients were investigated. TNF treatment on glioblastoma cells, even at a high dose (256 U/ml), exhibited no remarkable cytocidal activity in MTT assay, but at lower doses significantly inhibited colony forming and DNA synthesis. TNF at a low dose (10 U/ml) stimulated production of prostaglandin E2, Mn-superoxide dismutase, interleukin (IL)-6 and IL-8 by glioblastoma cells. These results indicated that the direct effect of TNF on human glioblastoma cells is rather antiproliferative than cytotoxic and is to modulate their metabolic pathways. In an early Phase I clinical trial, TNF was administered intracranially to six patients bearing glioblastoma. In this trial, the author studied in vivo immunological responses in the cerebrospinal fluid and regional fluid after the regional TNF injections. TNF in these body fluids were detected with a half life of several hours. There occurred a substantial number of leukocyte migration after the TNF administration. Neutrophils appeared first peaking at 8 to 12 hours, and then CD4+CD8-T cells and CD11b+CD13+CD14+ monocytes followed. IL-8 activity in the cerebrospinal fluid simultaneously corresponded to peak of the neutrophil migration. Increases in IL-6, IL-1 beta and prostaglandin E2 levels in the cerebrospinal fluid, regional fluid or both occurred peaking at 8 to 12 hours after TNA infection. Neither IL-2 nor interferons was detected. In conclusion, TNF may act as an antineoplastic agent by its direct cytostatic effects and indirectly through immune modulatory effects.
Tada
M
M
Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo, Japan.
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007276:Injections, Intraventricular; D009504:Neutrophils / Q000276:immunology; D013482:Superoxide Dismutase / Q000378:metabolism; D016176:T-Lymphocyte Subsets; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology*
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D015232:Dinoprostone