|Budget Amount *help
¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 1993: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1992: ¥2,600,000 (Direct Cost: ¥2,600,000)
In this study, various cytokines and bioactive molecules were studied ; productions of these growth factors by malignant gllioma cells and inversely the effect of exogenous factors on the tumor cells. In particular, glioma patients were investigated.
Human glioblastoma cells produced IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, G-CSF, SCF, PGE2, FGF, and PDGF.Glioblastoma cells expressed IL-1 receptors and p55TNF receptor. IL-1 and TNF had most remarkable effect on metabolism of the glioblastoma cells. TNF stimulation on glioblastoma cells, even at a high dose (256U-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 (10U/ml) stimulated production of PGE2, Mn-superoxide dismutase, IL-6 and IL-8 by flow cytometry. TNF arrested certain human glioma cells in the G0/G1 phase resulting in reduction of DNA synthesis in the subsequent S phase, suppressing the proliferation assay.
In an early Phase I clinical trial, TNF was administered intracranially to six parients 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 fluid 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 CDIIb+CD13+CD14+ monocytes followed. IL-8 activity in the cerebrospinal fluid simultaneously corresponded to the peak of the neutrophil migration Increases in IL-6, IL-1b and PGB2 levels in the cerebrospinal fluid, regional fluid or both occurred peaking at 8 to 12 hours after TNF injection. Neither IL-2 nor interfarons were detected. TNF may act as an antineoplastic agent by its direct cytostatic effects and indirectly through immune modulatry effects.