| Project/Area Number |
58870048
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
内科学一般
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
1983 – 1985
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| Project Status |
Completed (Fiscal Year 1985)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1985: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1984: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1983: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | Tumor Necrosis Factor (TNF) / Cytotoxic activity / Necrotizing activity / Lysosomal function / 血管内皮細胞障害 |
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| Research Abstract |
The mechanism of cytotoxic action and necrotizing action of TNF was examined. TNF activity could not be adsorbed by both TNF sensitive cell lines and TNF resistant cell lines from supernatant of the culture medium. Enzyme digestion of TNF sensitive cells failed to decrease the cytotoxic activity of TNF. TNF induced enhancement of the endogenous lysosome activity of tumor cells. Following addition of TNF, susceptible tumor cells revealed a decreased respiration after a certain period, and the respiration subsequently increased again. Superoxidase dismutase, sodium azide and sodium fluoride markedly increased the cytotoxicity of TNF. TNF increased the generation of <O(_2^-)> and other oxygen radicals in target tumor cells. These results suggest the importance of the myeloperoxidase system and glycolysis, that is, mitochondrial function and energy metabolism. The concentration of TNF acquiring in vitro cytotoxicity was 10 to 100 times higher than that reached in the blood for the in vivo necrotizing reaction. One of the reasons for this discrepancy is considered to be that TNF gives rise to changes involving endothelial cells. Histopathologically, the mechanism of tumor necrosis induced by TNF administration may be a hemorrhagic infarct due to circulatory disturbance associated with a microvascular injury manifested by hyperemia and multiple fibrin thrombi in vascular channels of tumor tissue. There were no pathologic changes in organs other than tumor tissue. However, TNF causes necrosis of granulation tissues. In vitro experiment, TNF exerts distinct physiological influences, such as morphological alteration, growth inhibition or cytotoxicity on the vascular endothelial cells.
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