To determine whether tumor necrosis factor is of potential value for the treatment of human malignant gliomas, we studied the effects of human recombinant tumor necrosis factor (rTNF-alpha) on the morphology, incorporation of tritiated thymidine, and proliferation of 5 established cell lines derived from human malignant gliomas and 3 normal human brain cell cultures. A radioreceptor analysis for rTNF-alpha was performed on all cell lines and cultures. Two of the 5 human glioma cell lines (SF-188 and U 343 MG-A) demonstrated a marked decrease (60% or less of untreated controls) in the uptake of tritiated thymidine when treated with rTNF-alpha at a concentration of 40 U/ml; rTNF-alpha at 100 U/ml had antiproliferative and cytotoxic effects on both cell lines. The growth and proliferation of cell lines SF-126 and U 251 MG were not affected by rTNF-alpha even at high concentrations (5,000 U/ml). The growth and proliferation of SF-539 were affected to an intermediate degree. A colony-forming efficiency assay corroborated the results of the proliferation studies: SF-126 was relatively resistant (surviving fraction of 0.9 at 500 U/ml) and SF-188 was relatively sensitive (surviving fraction of 0.08 at 500 U/ml) to the cytotoxic effects of rTNF-alpha. Time-sequence electron microscopy showed that rTNF-alpha at a concentration of 500 U/ml caused ultrastructural changes in SF-188, including increased intracytoplasmic vesiculation, swelling and degeneration of mitochondria, loss of cell:cell junctional complexes, and fragmentation of the plasma membrane. Studies with 125I-rTNF-alpha showed a variable degree of binding in all cell lines and cultures. SF-188, a highly sensitive cell line, demonstrated the strongest binding of 125I-rTNF-alpha (3,400 receptors/cell with high affinity; kd = 0.27 nM), while SF-126, a highly resistant cell line, had the weakest binding (809 receptors/cell; kd = 0.25 nM). We conclude that there is a spectrum of antiproliferative and cytotoxic activity among glioma-derived tumor cell lines exposed to rTNF-alpha. An increased number of rTNF-alpha receptors appears to be a necessary but insufficient condition to explain the antiproliferative effects observed in some glioma-derived cell lines.
To investigate the role of DNA interstrand crosslink formation on cytotoxicity and the induction of sister chromatid exchanges (SCEs), we treated 9L cells with the bifunctional mustard bis(2-chloroethyl)methylamine (HN2), which can alkylate DNA and form DNA interstrand crosslinks, or with two monofunctional mustards, bis(ethyl)-2-chloroethylamine and bis(methyl)-2-chloroethylamine, which can only alkylate DNA. On a molar basis, HN2 was 900-2400 times more cytotoxic and 471-686 times more effective at inducing SCEs than the monofunctional mustards. HN2 induced high levels of DNA interstrand crosslinks in 9L cells; no interstrand crosslinks were detected in cells treated with the monofunctional mustards. Comparison of the alkylating activity of each of the mustards by 4-(p-nitrobenzyl)pyridine reactivity showed only a 4-fold difference, which is not sufficient to account for the large differences in cell survival and induction of SCEs. We conclude that the effectiveness of HN2 at inducing cytotoxicity and SCEs results from the formation of DNA interstrand crosslinks.
Cilostazol is an antiplatelet aggregation inhibitor drug associated with increased cerebral blood flow and inflammation suppression. This study evaluated administration of cilostazol to prevent cerebral vasospasm following subarachnoid hemorrhage (SAH) in 50 patients treated surgically from December 2004 to November 2006. All patients, excluding those with Hunt and Kosnik grade 5 or who had undergone late surgery, were classified into two groups: 26 patients who received 200 mg/day cilostazol from postoperative day 1 to day 14 and 24 control patients. The frequency and the degree of cerebral vasospasm, occurrence of ischemic lesion, and clinical symptoms due to vasospasm were compared between the two groups. The appearance of severe vasospasm on angiography, persistent symptomatic spasm, and new cerebral infarction due to vasospasm demonstrated by neuroimaging were apparently lower in the cilostazol group than in the control group, suggesting that cilostazol may significantly suppress cerebral vasospasm following SAH.
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