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At least 73 records · Page 4Linked to original sources
PubMed1998

Complete response of melanoma-in-transit metastasis after isolated limb perfusion with tumor necrosis factor alpha and melphalan without massive tumor necrosis: a clinical and histopathological study of the delayed-type reaction pattern.

Treatment of stage IIIA/B melanoma patients by isolated limb perfusion (ILP) with a combination of tumor necrosis factor-alpha (TNF-alpha) and melphalan induces a complete response in 80-90% of the cases. The mechanism of tumor regression induced by the combination of TNF-alpha and melphalan is not precisely understood. Previous studies focused on the immediate (ie., within a few days) clinico-pathological changes after perfusion involving hemorrhagic necrosis. However, clinical data clearly indicate that complete tumor remission frequently requires a period of a few weeks to as much as months after ILP. Because the mechanism underlying this delayed-type reaction is completely unknown, we studied the clinico-pathological events in patients with such slowly regressing melanoma lesions. For this purpose, 94 biopsies of in-transit melanoma metastasis that were taken sequentially from 11 patients between 1 week and 9 months after ILP were analyzed by light and electron microscopy and immunohistochemistry. Clinical data included patient sex, age, anatomical localization and size of the tumor, and follow-up. All of the 11 patients ultimately responded to perfusion treatment (9 complete, 1 partial, 1 stable disease). Serial biopsies showed scattered individual tumor cell necrosis without hemorrhage. Most of the lesions with this delayed-type reaction pattern were less than 0.5 cm in diameter. They contained varying amounts of histologically viable-looking tumor cells and tumor-infiltrating melanophages. In addition, a marked but transient infiltrate of peritumoral eosinophils and moderate interstitial edema and dermal fibrosis were encountered. Only small numbers of lymphocytes were present. In comparison with the reaction pattern after treatment with melphalan alone, the delayed-type reaction pattern was similar but more intense. The scattered tumor cell necrosis in the latter type may be explained by a TNF-alpha-induced increase in permeability of the tumor vascular bed, which results in higher intratumoral concentrations of melphalan or in a prolongation of its effect. Subsequently, degenerated tumor cells are cleared by macrophages, and, finally, repair by fibrosis occurs. Because the immediate reaction type is evoked by hyperpermeability of the tumor vessels as well, quantitative differences seem to determine which reaction type ensues. We suggest that the extent of tumor vasculature that is sensitive to TNF-alpha determines the onset and histopathological pattern of tumor regression after ILP.

Aged↗
PubMed1995

Glycosylated recombinant human tumor necrosis factor binding protein-1 reduces mortality, shock, and production of tumor necrosis factor in rabbit Escherichia coli sepsis.

OBJECTIVE: To examine the effect of glycosylated recombinant human tumor necrosis factor binding protein-1 (r-hTNF binding protein-1), the extracellular domain of the tumor necrosis factor receptor p55 produced in mammalian cells, in a rabbit model of circulatory shock due to Escherichia coli. DESIGN: Prospective, randomized, controlled trial. SETTING: University hospital research laboratory. SUBJECTS: Eighteen female, New Zealand white rabbits. INTERVENTIONS: Anesthetized rabbits, infused with E. coli (10(9) organisms/kg), were pretreated with either r-hTNF binding protein-1 or saline. Mean arterial pressure, central venous pressure, cardiac output, and heart rate were recorded every 20 mins for 1 hr before, and for 4 hrs after, the infusion of E. coli. Blood samples were obtained at 1-hr intervals for platelet count and white blood cell count, r-hTNF binding protein-1, and tumor necrosis factor (TNF) measurements. MEASUREMENTS AND MAIN RESULTS: Administration of r-hTNF binding protein-1 resulted in improvement of mean arterial pressure, cardiac output, and systemic vascular resistance, as compared with the vehicle-treated group (p < .05). Treatment with r-hTNF binding protein-1 was associated with 100% survival, as compared with 55.6% of the saline-treated rabbits (p < .05). Approximately 85% of r-hTNF binding protein-1 was cleared from the circulation 1 hr after the bolus injection (from 171 +/- 27 micrograms/mL at time = 0, to 27 +/- 4 micrograms/mL at 60 mins, decreasing to 6 +/- 2 micrograms/mL for the next 3 hrs). The r-hTNF binding protein-1-treated rabbits had lower serum TNF bioactivity during the first 2 hrs (p < .01). The decreased bioactivity of TNF was confirmed by a specific radioimmunoassay for rabbit TNF. However, at 4 hrs, the vehicle-treated rabbits had lower serum bioactive TNF concentrations (p < .05). The decrease in TNF concentrations in the r-hTNF binding protein-1-treated rabbits resulted from decreased production and, in part, from carry-over of r-hTNF binding protein-1 into the bioassay. CONCLUSIONS: Treatment with r-hTNF binding protein-1 improved hemodynamic variables and survival of E. coli-challenged rabbits. Administration of r-hTNF binding protein-1 suppressed bioactivity of TNF in the circulation of these rabbits, and the production of TNF as well.

Animals↗
PubMed1991

Shifting necrosis: butylated hydroxytoluene (BHT) and phenobarbital move cocaine-induced hepatic necrosis across the lobule.

Cocaine (60 mg/kg i.p.) caused centrilobular necrosis in the livers of 55% of DBA/2Ha mice. Pretreatment with phenobarbital (PB, 3 x 80 mg/kg i.p.) increased the incidence of necrosis to 70% and shifted this damage to the midzonal region. Pretreatment with butylated hydroxytoluene (BHT, 0.1% in diet) increased the severity of the centrilobular damage and increased the incidence to 90%. Combined treatment with both PB and BHT shifted the site of necrosis to the periportal region of the liver, and induced necrosis in all animals. Microsomal malondialdehyde (MDA) did not reflect the extent of the damage and/or correlate with the site of damage. These results argue against a causal role for lipid peroxidation in the mechanism of cocaine hepatotoxicity, and demonstrate that prior exposure to enzyme-inducing agents can increase sensitivity and dramatically alter the site of cell damage.

Alanine Transaminase↗
PubMed2000

The effect of heat- and auto-polymerized denture base polymers on clonogenicity, apoptosis, and necrosis in fibroblasts: denture base polymers induce apoptosis and necrosis.

Eluates from poly(methyl methacrylate)-based denture base polymers have recently been found to enhance death by apoptosis and necrosis in U-937 human monoblastoid cells. The present study investigated the potential of such polymers to induce apoptosis and/or necrosis and to alter clonogenicity in L929 murine fibroblasts. A fibroblast cell line was chosen because the impairment of fibroblasts subjacent to denture bases may result in a weaker or more permeable mucosa. Two aspects were addressed: the effect of direct contact with the denture base polymers and the effect of eluates extracted from the polymers. For this purpose L929 fibroblasts were seeded on disks manufactured from three heat-polymerized and four autopolymerized denture base polymers or in different concentrations of their eluates. The effects were evaluated by light, fluorescent, confocal and electron microscopy, counting of colonies, and flow cytometry. Disks and eluates of all polymers enhanced cell death by apoptosis and necrosis in L929 cells and decreased their clonogenic potential in a dose-dependent manner. Apoptosis was the main form of cell death. In general, the deleterious effects were stronger when cells were plated directly on the polymer disks than in the eluates. The autopolymerized polymers, except one, yielded higher percentages of apoptosis and necrosis than the heat-polymerized polymers. The results of the study indicated that poly(methyl methacrylate)-based denture base polymers trigger death-signals in L929 fibroblasts and open doors for possible modulation of the cell/biomaterial interaction.

Animals↗
PubMed2006

Graft tumor necrosis factor receptor-1 protects after mouse liver transplantation whereas host tumor necrosis factor receptor-1 promotes injury.

BACKGROUND: Tumor necrosis factor (TNF)-alpha is a cytokine with pleiotropic effects on the liver. The predominant hepatic receptor for TNFalpha is TNF receptor-1 (TNFR1). TNFR1 mediates liver injury after ischemia/reperfusion but is also mitogenic during hepatic regeneration. This study investigated the role of graft and host TNFR1 in early graft injury after liver transplantation in mice. METHODS: Livers from TNFR1 deficient (TNFR1-/-) and wild type (WT) mice were transplanted into either TNFR1-/- or WT recipients in all four possible combinations after 12 hours of cold storage. After eight hours, alanine transferase (ALT), necrosis, TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining, caspase-3 activation, and myeloperoxidase were determined. RESULTS: When TNFR1-/- livers were transplanted into either WT or TNFR1-/- recipients, ALT was twofold greater than when WT donor livers were used. Necrosis and TUNEL staining also increased twofold and sevenfold, respectively, after transplantation of TNFR1-/- donor livers compared to WT. By contrast, ALT and necrosis decreased when WT or TNFR1-/- livers were transplanted into TNFR1-/- hosts compared to WT, which was associated with decreased neutrophil infiltration. CONCLUSION: In conclusion, graft and recipient TNFR1 has opposing effects. Graft TNFR1 decreases graft injury, whereas recipient TNFR1 mediates an increase of injury associated with enhanced neutrophil infiltration. Cross-transplanting of knockout and wild-type livers provides a new means to investigate graft-host interactions during hepatic injury.

Alanine Transaminase↗
PubMed1991

[Bile duct necrosis and hepatic necrosis following hepatic arterial infusion chemotherapy].

Three cases of bile duct necrosis owing to hepatic arterial infusion chemotherapy (HAI) were reported. Regarding HAI, transcatheter hepatic arterial embolization (TAE) was applied in two cases (hepatocellular carcinoma: 1; metastasis: 1) and 5-fluorouracil (continuous) combined with leucovorin (one shot) therapy (LV + 5-FU) was given to one metastatic case. In the data of blood biochemistry, serum alkaline phosphatase, gamma-glutamyl transpeptidase, and leucine aminopeptidase values characteristically elevated without the elevation of total bilirubin value. Hepatic tumors degenerated with necrosis in all cases and no viable cells were histologically recognized. Although the destruction of bile ducts was locally detected adjacent to these tumors in TAE cases and was more widespread in the LV + 5-FU case, these lesions were very similar in each case. Therefore, we concluded that both ischemia and drug toxicity induced bile duct necrosis and the necrosis around the bile duct was the secondary change due to the leaked bile juice.

Aged↗
PubMed1996

Avascular necrosis and the Pavlik harness. The incidence of avascular necrosis in three types of congenital dislocation of the hip as classified by ultrasound.

We analysed the incidence of avascular necrosis in 101 hips of 90 infants with congenital dislocation treated with Pavlik harness and followed up for more than one year. Using ultrasonography in the flexed-abducted position the hips were classified as type A when the femora head was displaced posteriorly, but within the socket and making contact with the posterior inner wall of the acetabulum; type B when it was in contact with the posterior margin of the acetabulum, with its centre at this level or anterior to it; and type C when it was displaced out of the socket, with its centre posterior to the posterior rim of the acetabulum. Eighty-seven hips were reduced by the harness (86%), and seven of these developed avascular necrosis (8%). All 69 hips with type-A dislocation were reduced and only one (1.4%) showed slight avascular necrosis. Eighteen (78.3%) of 23 hips with type-B dislocation were reduced, and six developed avascular necrosis (33.3%). In one hip, the femoral head was severely damaged. None of the nine hips with type-C dislocation was reduced in the harness. We concluded that the Pavlik harness is indicated for type-A but not for type-B or type-C dislocations.

Contraindications↗
PubMed2004

Involvement of tumor necrosis factor-alpha receptor 1 and tumor necrosis factor-related apoptosis-inducing ligand-(TRAIL) receptor-2/DR-5, but not Fas, in graft injury in live-donor liver transplantation.

The pathway leading to cell death in clinical liver transplantation is not known. Eight liver transplant recipients and eight donors were enrolled in this study. Postoperative serum levels of alanine transferase had significantly increased in the recipients compared with those in the donors. Mild centri-lobular necrosis was observed in only liver tissues taken from the recipients. Tumor necrosis factor (TNF)-R1 and death receptor 5 expression levels had increased in liver tissues taken from the recipients. There were no changes in the levels of Fas/Fas ligand expression in liver tissues from either the donors or recipients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression was down-regulated in donor liver after hepatectomy and liver allograft after implantation. The results suggest that, although ischemic liver injury was not serious, due to the short ischemia time, TNF and TRAIL signals are associated with liver ischemic injury in live-donor liver transplantation but Fas signal is not.

Apoptosis↗
PubMed2006

The role of soluble tumor necrosis factor receptor types I and II and tumor necrosis factor-alpha in malaria during pregnancy.

In a prospective study of rhesus monkeys inoculated with Plasmodium coatneyi or saline on an infection/gestational timeline, we determined the serum levels of tumor necrosis factor-alpha (TNF-alpha), soluble tumor necrosis factor receptor type I (sTNFR-I), and soluble tumor necrosis factor receptor type II (sTNFR-II) in peripheral blood throughout primigravid pregnancy, malaria infection, and a combination of the two. Our goal was to determine the association between levels of TNF-alpha and of its 2 soluble receptors and the course of pregnancy and/or malaria and infant outcome. We found that any detectable level of TNF-alpha was always associated with fetal death and that the sTNFRs may be important for fetal protection, possibly through neutralizing the toxic effects of TNF-alpha. Our findings also showed that increased levels of sTNFR-II were associated specifically with malaria and not with normal pregnancy or even pregnancy with low birth weight due to other causes. In contrast, increases in sTNFR-I levels during the later half of normal pregnancies indicate that sTNFR-I may be important in regulating TNF-alpha levels in preparation for normal labor and delivery.

Animals↗
PubMed1979

Cell killing by spleen necrosis virus is correlated with a transient accumulation of spleen necrosis virus DNA.

Spleen necrosis virus productively infects avian and rat cells. The average number of molecules of unintegrated and integrated viral DNA in cells at different times after infection was determined by hybridization and transfection assays. Shortly after infection, there was a transient accumulation of an average of about 150 to 200 molecules of unintegrated linear spleen necrosis virus DNA per chicken, turkey, or pheasant cell. No such accumulation was seen in infected rat cells. Soon after infection there was in chicken cells, but not inturkey, pheasant, or rat cells, also a transient integration of an average of 35 copies of viral DNA per cell. By 10 days after infection, the majority of this integrated viral DNA was lost from the population of infected chicken cells. At the same time, the majority of the unintegrated viral DNA was also lost from infected chicken, turkey, and pheasant cells. The transient cytopathic effect seen in these infected cells also occurred at this time. Late after infection about five copies of apparently nondefective spleen necrosis proviruses were stably integrated at multiple sites in chicken, turkey, pheasant, and rat DNA. These results demonstrate a correlation between the transient accumulation of large numbers of spleen necrosis virus DNA molecules and the transient occurrence of cytopathic effects.

Animals↗
PubMed2002

Bone marrow necrosis with dyspnea in a patient with malignant lymphoma and plasma levels of thrombomodulin, tumor necrosis factor-alpha, and D-dimer.

Non-Hodgkin's lymphoma (peripheral T cell, unspecified, clinical stage IIIEA) was diagnosed in a 54-year-old male. He was treated weekly with chemotherapy consisting of pirarubicin hydrochloride, cyclophosphamide, methotrexate, vincristine sulfate, etoposide, and prednisolone. After 6 weeks of treatment in a state of partial remission, he exhibited sudden dyspnea, chest pain, fever, and drowsiness. The patient had received 100 microg/day of granulocyte colony stimulating factor (G-CSF) for 6 days before the onset. Laboratory data showed an elevated lactate dehydrogenase (LDH) level, leukoerythroblastosis in the peripheral blood, and no decrease in the serum haptoglobin level. There were no findings of acute myocardial infarction or pulmonary thromboembolism. Bone marrow specimen showed the characteristic features of necrosis without any signs of the involvement of lymphoma cells. No indications of infections were found. This patient was diagnosed as having bone marrow necrosis (BMN) during the recovery phase of bone marrow with G-CSF treatment after chemotherapy for malignant lymphoma. After conservative therapy, inhalation of oxygen and stopping the administration of G-CSF, all clinical symptoms subsided except that the elevation of LDH continued for 1 month. The plasma level of tumor necrosis factor-alpha (TNF-alpha) was high just after the onset of BMN. The thrombomodulin (TM) level was high just before the onset of BMN and continued to be high for 2 weeks. Cross-linked fibrin degradation products (D-dimer) were also high just after the onset of BMN and continued to be high for 3 weeks after the onset. Although dyspnea is a rare symptom of BMN, it is important to rule out in BMN during the recovery phase of bone marrow with G-CSF treatment after chemotherapy for malignant lymphoma. Activated neutrophils in the small vessels of the lung by G-CSF and microthrombi, suggested by the elevation of D-dimer, may participate in the onset of dyspnea, which is a rare symptom of the onset of BMN.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant.

OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A). The purpose of this study was to describe a novel TNFRSF1A mutation (C43S) in a patient with TRAPS and to examine the effects of this TNFRSF1A mutation on tumor necrosis factor alpha (TNFalpha)-induced signaling in a patient-derived primary dermal fibroblast line. METHODS: TNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Primary dermal fibroblast lines were established from the patient with the C43S TRAPS mutation and from healthy volunteers. Activation of NF-kappaB and activator protein 1 (AP-1) was evaluated by electrophoretic mobility shift assays. Cytokine production was measured by ELISA. Cell viability was measured by alamar blue assay. Apoptosis was measured by caspase 3 assay in the fibroblasts and by annexin V assay in peripheral blood mononuclear cells. RESULTS: Activation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation. TNFalpha-induced activation of NF-kappaB and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation. Nevertheless, the C43S TRAPS fibroblasts were capable of producing interleukin-6 (IL-6) and IL-8 in response to TNFalpha. However, TNFalpha-induced cell death and apoptosis were significantly decreased in the samples from the patient with the C43S TRAPS mutation. CONCLUSION: The C43S TNFRSF1A mutation results in decreased TNFalpha-induced nuclear signaling and apoptosis. Our data suggest a new hypothesis, in that the C43S TRAPS mutation may cause the inflammatory phenotype by increasing resistance to TNFalpha-induced apoptosis.

Apoptosis↗
PubMed1997

Tumour necrosis factor-induced necrosis versus anti-Fas-induced apoptosis in L929 cells.

Murine fibrosarcoma L929 cells were transfected with human Fas cDNA. The mode of cell death was analysed following treatment either with tumour necrosis factor (TNF) or with agonistic antibodies to Fas. While triggering of the TNF receptors led to necrosis, clustering of the Fas antigen resulted in apoptotic cell death. N-tosyl-l-phenylalanine chloromethyl ketone and Nalpha-p-tosyl-l-lysine chloromethyl ketone, two serine protease inhibitors, has a protective effect on TNF-induced killing, while Fas-mediated cell death was rather enhanced. Lithium chloride, which had a synergistic effect on TNF cytotoxicity, did not affect Fas-mediated death, whereas staurosporine had an enhancing effect on both types of cell death. Aphidicolin and hydroxyurea, inhibitors of DNA synthesis, were able to sensitize cells to Fas-induced killing, but had no effect on TNF cytotoxicity. Finally, we demonstrate that the effect of increasing concentrations of actinomycin D or cycloheximide is very different for the two types of cell killing. We conclude that either necrosis or apoptosis can occur in the same cell type, depending on the trigger, and that, although both pathways perhaps may share some cellular components, signal transduction is different for the two types of cell death.

Adjuvants, Immunologic↗
PubMed1995

Quinine inhibits release of tumor necrosis factor, apoptosis, necrosis and mortality in a murine model of septic liver failure.

We investigated the effect of quinine on liver injury induced by lipopolysaccharide in mice sensitized with D-galactosamine. This model is characterized by high systemic release of tumor necrosis factor, which mediates hepatic apoptosis and necrosis. Pretreatment with quinine, a K+ channel blocker, prevented formation of tumor necrosis factor (TNF) as well as the subsequent hepatic DNA fragmentation and liver enzyme leakage. Thus, inhibition of K+ channels may be a novel therapeutic approach in cytokine-related organ damage.

Animals↗
PubMed2004

Necrosis of infectious pancreatic necrosis virus (IPNV) infected cells rarely is preceded by apoptosis.

Infectious pancreatic necrosis virus (IPNV)-infected cells were labeled with Annexin V and propidium iodide in order to determine the proportion of cells, which developed necrosis and/or apoptosis during the time course of infection. Contrasting with earlier reports, we found that at any time during IPNV multiplication cycle, the percentage of apoptotic cells never exceeded the 12% of the whole population of the infected cells. In addition, the percentage of necrotic cells increased continuously until reaching the 75% of the infected cells at 15 h post infection. Apoptotic cells were also identified by in situ terminal deoxynucleotidyl transferase-mediated BrdUTP nick end labeling (TUNEL). Our results are in accordance with the idea that apoptosis rarely precedes necrosis.

Animals↗
PubMed2001

Interferon gamma (IFNgamma ) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways.

We investigated the molecular mechanism of the synergism between interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) documented in a variety of biological occasions such as tumor cell death and inflammatory responses. IFNgamma/TNFalpha synergistically induced apoptosis of ME-180 cervical cancer cells. IFNgamma induced STAT1 phosphorylation and interferon regulatory factor 1 (IRF-1) expression. Transfection of phosphorylation-defective STAT1 inhibited IFNgamma/TNFalpha-induced apoptosis, whereas IRF-1 transfection induced susceptibility to TNFalpha. Dominant-negative IkappaBalpha transfection sensitized ME-180 cells to TNFalpha. IFNgamma pretreatment attenuated TNFalpha- or p65-induced NF-kappaB reporter activity, whereas it did not inhibit p65 translocation or DNA binding of NF-kappaB. IRF-1 transfection alone inhibited TNFalpha-induced NF-kappaB activity, which was reversed by coactivator p300 overexpression. Caspases were activated by IFNgamma/TNFalpha combination; however, caspase inhibition did not abrogate IFNgamma/TNFalpha-induced cell death. Instead, caspase inhibitors directed IFNgamma/TNFalpha-treated ME-180 cells to undergo necrosis, as demonstrated by Hoechst 33258/propidium iodide staining and electron microscopy. Taken together, our results indicate that IFNgamma and TNFalpha synergistically act to destroy ME-180 tumor cells by either apoptosis or necrosis, depending on caspase activation, and STAT1/IRF-1 pathways initiated by IFNgamma play a critical role in IFNgamma/TNFalpha synergism by inhibiting cytoprotective NF-kappaB. IFNgamma/TNFalpha synergism appears to activate cell death machinery independently of caspase activation, and caspase activation seems to merely determine the mode of cell death.

Apoptosis↗
PubMed1988

The antitumor function of tumor necrosis factor (TNF) II. Analysis of the role of endogenous TNF in endotoxin-induced hemorrhagic necrosis and regression of an established sarcoma.

In agreement with the results of previous studies (1), it was shown that intravenous injection of endotoxin into mice bearing 9-d SA1 sarcoma resulted in a tumor hemorrhagic reaction that rapidly caused necrosis of most of the center of the tumor, and then the complete regression of the rim of living tumor tissue that survived the hemorrhagic reaction. The tumor hemorrhagic reaction was confined to the vascular bed of the tumor, and its rate and extent of development were measured in terms of the intratumor extravasation of 51Cr-labeled syngeneic red cells. The development of the hemorrhagic reaction was associated with the presence in the tumor over a 6-h period of endogenous TNF that was measured in terms of its capacity to kill L929B cells in vitro and identified by its susceptibility to neutralization with a monospecific, polyvalent anti-rTNF antibody. The same antibody was capable in vivo of inhibiting the endotoxin-induced tumor hemorrhagic reaction by only approximately 50%, even when present in the tumor in excess. However, it was capable when given in the same quantity of inhibiting the ability of endotoxin to cause complete tumor regression. The fact that TNF was generated in the tumor during the tumor hemorrhagic reaction, and that infusion of a sufficient quantity of anti-rTNF antibody severely interfered with hemorrhagic necrosis and prevented tumor regression represents convincing evidence that TNF is an essential participant in endotoxin-induced regression of an established SA1 sarcoma. Moreover, because tumor regression, as opposed to hemorrhagic necrosis, failed to occur if the tumor was growing in immunoincompetent mice, but did so if the mice were infused with tumor-sensitized T cells, it can be concluded that an adequate level of T cell-mediated immunity is also an essential requirement for endotoxin-induced tumor regression. The participation of other endotoxin-induced mediators in tumor regression cannot be ruled out.

Animals↗
PubMed1998

Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor.

Murine L929 fibrosarcoma cells treated with tumor necrosis factor (TNF) rapidly die in a necrotic way, due to excessive formation of reactive oxygen intermediates. We investigated the role of caspases in the necrotic cell death pathway. When the cytokine response modifier A (CrmA), a serpin-like caspase inhibitor of viral origin, was stably overexpressed in L929 cells, the latter became 1,000-fold more sensitive to TNF-mediated cell death. In addition, TNF sensitization was also observed when the cells were pretreated with Ac-YVAD-cmk or zDEVD-fmk, which inhibits caspase-1- and caspase-3-like proteases, respectively. zVAD-fmk and zD-fmk, two broad-spectrum inhibitors of caspases, also rendered the cells more sensitive, since the half-maximal dose for TNF-mediated necrosis decreased by a factor of 1,000. The presence of zVAD-fmk also resulted in a more rapid increase of TNF-mediated production of oxygen radicals. zVAD-fmk-dependent sensitization of TNF cytotoxicity could be completely inhibited by the oxygen radical scavenger butylated hydroxyanisole. These results indicate an involvement of caspases in protection against TNF-induced formation of oxygen radicals and necrosis.

Amino Acid Chloromethyl Ketones↗