Dexamethasone inhibits the cytotoxic activity of tumor necrosis factor

Tsujimoto, Masafumi; Okamura, Nobutaka; Adachi, Hideki

doi:10.1016/s0006-291x(88)81196-3

Cited by 22 publications

(12 citation statements)

References 28 publications

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“…It has been reported that actions of DM such as TNF receptor down-modulation (Kull, 1988) and phospholipase-A2 inhibition (Neale et al, 1988) decrease the TNF susceptibility of cells (Tsujimoto et al, 1988); and in this study we noticed that the IC,, increased approximately 2-fold in L-M cells treated with DM. In LM(pNTnF) cells, after induction of enTNF by DM, the IC,, value increased approximately 5-to 14-fold.…”

Section: Discussionsupporting

confidence: 66%

Induction of synthesis of manganous superoxide dismutase in L‐M(pNtnF) cells carrying an inducible TNF gene

Himeno

Watanabe

Yamauchi

et al. 1992

Intl Journal of Cancer

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Based on findings that the cytotoxic effects of tumor necrosis factor (TNF) are closely related to levels of intracellular oxygen radicals, and on the results of TNF gene transfection studies, the hypothesis was made that endogenous TNF (enTNF) acts as a protective factor against exogenous TNF by inducing inhibitors or scavengers of oxygen radicals. In order to test this hypothesis, we investigated the intracellular levels of manganous superoxide dismutase (MnSOD) and glutathione (GSH) in L-M(pNTnF) cells carrying a TNF gene induced by dexamethasone (DM). When L-M(pNTnF) cells were treated with DM they expressed enTNF, and acquired resistance to exogenous TNF. There was no change in the GSH concentration after enTNF induction, but a 1.9- to 3.9-fold increase in MnSOD levels was noted. Our findings suggest that enTNF exerts its protective function against the cytocidal effect of exogenous TNF by inducing MnSOD production.

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Section: Discussionsupporting

confidence: 66%

Induction of synthesis of manganous superoxide dismutase in L‐M(pNtnF) cells carrying an inducible TNF gene

Himeno

Watanabe

Yamauchi

et al. 1992

Intl Journal of Cancer

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“…Quinacrine was the most effective inhibitor of cell destruction, followed by hydrocortisone, dexamethasone, and indomethacin. Other investigators have also found that these inhibitors block TNF-induced cytotoxicity, with even more potent effects (close to 100% inhibition of cytotoxicity) (Abe et al, 1988;Tsujimoto et al, 1988). These inhibitor studies rule out the possibility that PLase activation occurs after cell destruction as a result of death.…”

Section: Discussionmentioning

confidence: 90%

Mechanism of human lymphotoxin and tumor necrosis factor induced destruction of cells in vitro: Phospholipase activation and deacylation of specific‐membrane phospholipids

Knauer

Longmuir

Yamamoto

et al. 1990

Journal Cellular Physiology

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The role of phospholipase (PLase) activation and lipid metabolism in lymphotoxin (LT)- and tumor necrosis factor (TNF)-mediated destruction of murine L929 cells was examined. At the levels of LT and TNF employed, cell destruction began at 4-6 h and was 99% complete by 30 h. Cell membrane phospholipids (PL), labelled in situ at the C2 position with 14C arachidonic acid, were analyzed by two-dimensional thin-layer chromatography and quantitated over a 30 h time course after LT or TNF treatment. The ratio of radiolabel incorporation relative to the actual amount of each PL present was determined by inorganic phosphate analysis. Radiolabelled arachidonic acid, eicosanoids, and neutral lipids were released into the medium prior to the onset of cell death (4-6 h) and continued to accumulate linearly throughout the destructive reaction. There was a quantitative relationship between the appearance of radiolabelled metabolites in the media and the loss of radiolabelled cellular PL. Cellular phosphatidylethanolamine was the primary PL deacylated by PLase action, showing a 75% reduction in radiolabel. The PLase inhibitors--quinacrine, hydrocortisone, dexamethasone, and indomethacin--were potent inhibitors of LT- and TNF-mediated cell destruction, suggesting that selective deacylation of specific membrane PL by PLase activation is an important step in the events that lead to LT- and TNF-mediated cellular destruction in vitro.

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“…The narrow therapeutic index of TNF-o~ has encouraged the development of strategies to diminish toxicity while hopefully preserving antitumor activity. Several approaches include use of continuous infusions (13), glucocorticoids (14), inhibitors of prostaglandin synthesis (15), scavengers of oxygen radicals (16), and combining TNF-ot with cytotoxic chemotherapy (17) or other cytokines (18). Toxicity still remains the most significant limitation to TNF-c~ therapeutic utility.…”

Section: Sul-lrlmarymentioning

confidence: 99%

Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality.

Hrushesky

Langevin

Kim

et al. 1994

The Journal of Experimental Medicine

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Sul-lrlmaryRecombinant human tumor necrosis factor-o~ (TNF-c~) has demonstrable antitumor activity in transplantable murine tumor models and patients with cancer but is highly toxic to both animals and human beings. The narrow therapeutic index of TNF-cx has limited its anticancer utility. Toxicity associated with many standard anticancer drugs is highly dependent upon the circadian timing of their administration. The effect of time of day of TNF-o~ administration on lethal toxicity was examined in 238 BALB/c female mice in two studies. Each mouse received a single intravenous injection of human TNF-c~ at one of six equispaced times within the first contiguous 24-h cycle. The probability of dying across all times of day of TNF-c~ treatment was not equal (p <0.01) and varied up to ninefold. Significant time of day dependence of TNF-cx toxicity was present over a full order of magnitude of TNF-ot dose. The frequency of TNF-a-induced lethality was greatest and the time to death was most brief when TNF-a was administered just before awakening. The survival probability was highest when TNF-o~ was administered in the second half of the daily activity span corresponding roughly to late afternoon and evening hours for human beings. The optimization of TNF-c~ administration timing is a strategy that warrants further investigation for improving the toxic/therapeutic ratio of this important cytokine. From a more fundamental perspective, these data may be essential for achieving a fuller understanding of TNF-o~ in vivo biology.

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Dexamethasone inhibits the cytotoxic activity of tumor necrosis factor

Cited by 22 publications

References 28 publications

Induction of synthesis of manganous superoxide dismutase in L‐M(pNtnF) cells carrying an inducible TNF gene

Induction of synthesis of manganous superoxide dismutase in L‐M(pNtnF) cells carrying an inducible TNF gene

Mechanism of human lymphotoxin and tumor necrosis factor induced destruction of cells in vitro: Phospholipase activation and deacylation of specific‐membrane phospholipids

Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality.

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