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PubMed1994

Regulation of tumor necrosis factor-alpha-mRNA synthesis and distribution of tumor necrosis factor-alpha-mRNA synthesizing cells in rat liver during experimental endotoxemia.

Stimulated liver macrophages (Kupffer cells) are known to release a variety of inflammation-related substances, e.g. cytokines, prostanoids, and reactive oxygen intermediates. For instance, exposure of Kupffer cells in vitro to lipopolysaccharide (endotoxin) leads to a strongly enhanced synthesis of the mRNA for tumor necrosis factor-alpha, the release of the mature protein into culture media. These events are influenced by prostanoids and corticoid hormones. Kupffer cells are thought to be the only source of tumor necrosis factor-alpha within the hepatic sinusoid, but neither this cell specificity nor the regulatory influence of glucocorticoids or prostanoids has been confirmed in the intact organ. Using non-radioactive in situ hybridization, it was possible to obtain specific signals for tumor necrosis factor-alpha-mRNA in individual Kupffer cells uniformly distributed (as compared to Kupffer cells detected by immunohistochemistry) throughout the liver. Kupffer cells were the only cells in the hepatic sinusoids of lipopolysaccharide-perfused livers to express mRNA for tumor necrosis factor-alpha. Simultaneous addition of endotoxin plus dexamethasone and endotoxin and prostaglandin E2 completely suppressed the synthesis of this mRNA. Unexpectedly, the presence of mRNA for tumor necrosis factor-alpha was also detected in the intrahepatic bile duct epithelium of lipopolysaccharide-perfused livers. It is known that biologically active endotoxin is secreted via the bile ducts. These results seem to indicate that bile duct epithelium responds to inflammatory agents with synthesis of tumor necrosis factor-alpha-mRNA. One must also consider new functional aspects of bile duct epithelium in chronic inflammatory diseases, e.g. primary biliary cirrhosis, chronic sclerosing cholangitis or graft-versus-host disease.

Animals↗
PubMed2003

Detection and quantification of breast tumor necrosis with MR imaging: value of the necrosis-avid contrast agent Gadophrin-3.

RATIONALE AND OBJECTIVES: The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS: Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS: In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION: Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

Animals↗
PubMed1990

Diphenylamine-induced renal papillary necrosis and necrosis of the pars recta in laboratory rodents.

The nephrotoxicity of diphenylamine, the parent compound of the mefenamate family of nonsteroidal anti-inflammatory drugs, was evaluated in male Syrian hamsters, male Sprague-Dawley rats, and male Mongolian gerbils. Total renal papillary necrosis was observed in four of ten, seven of ten, and six of ten male Syrian hamsters orally treated with diphenylamine at respective doses of 400 mg/kg body weight/day, 600 mg/kg body weight/day, and 800 mg/kg body weight/day. Total renal papillary necrosis was also observed in five of ten and four of ten male Syrian hamsters intraperitoneally treated with diphenylamine at respective doses of 600 mg/kg body weight/day and 800 mg/kg body weight/day. Focal intermediate renal papillary necrosis was induced in two hamsters orally given diphenylamine at 600 mg/kg body weight/day and in two of ten hamsters intraperitoneally given diphenylamine at 800 mg/kg body weight/day. Apex-limited necrosis of the medullary interstitial cells and vasa recta and degeneration of the renal interstitial matrix occurred in two Sprague-Dawley rats orally administered diphenylamine at 800 mg/kg body weight/day. Degeneration and necrosis of the pars recta was induced in seven of ten hamsters intraperitoneally given diphenylamine at 400 mg/kg body weight/day. Gross and microscopic renal lesions were not observed in any Mongolian gerbils. It was concluded that the Syrian hamster is more susceptible to the papillotoxic effects of diphenylamine than the Sprague-Dawley rat and the Mongolian gerbil. Renal papillary necrosis in the Syrian hamster treated orally with diphenylamine is reproducible, is of short onset, and is induced in a high proportion of the hamsters (70-90%).(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗
PubMed2000

Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis.

Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, reports have described prevention of hepatic necrosis, induced by other hepato-toxins, by inhibiting tumour necrosis factor alpha (TNFalpha). The aim of the present study was to determine the role of TNFalpha in paracetamol-induced hepatic necrosis. Six-week-old CBA/J female mice were given 300 mg/kg paracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic expression of TNFalpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum TNFalpha was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, interleukin 10 (IL-10), and dexamethasone. Hepatic injury was measured by serum aspartate aminotransferase and histological assessment on haematoxylin and eosin (H&E)-stained liver sections. There was a significant increase in serum TNFalpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treated 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNFalpha expression did not change up to 24 h following paracetamol injection. Histologically severe centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h after paracetamol poisoning. Death rate, serum aspartate aminotransferase, and hepatic histology were not significantly different between the groups treated with blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, IL-10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFalpha expression affects hepatic injury following experimental paracetamol poisoning; anti-TNFalpha therapies are therefore unlikely to be effective in the corresponding clinical situation.

Acetaminophen↗
PubMed1991

Acute hemorrhagic necrosis of tumors induced by interleukin-1 alpha: effects independent of tumor necrosis factor.

Tumor necrosis factor (TNF), a protein synthesized in response to the endotoxin bacterial lipopolysaccharide (LPS), is the classical mediator of acute hemorrhagic necrosis of tumors. We have demonstrated that interleukin-1 alpha (IL-1 alpha), with a spectrum of activities very similar to those of TNF, also causes acute hemorrhagic necrosis of tumors. Both TNF and IL-1 induce a cascade of events including the synthesis or release of each other. The present studies were thus undertaken to determine whether the hemorrhagic necrosis induced in tumors by IL-1 alpha is due to TNF. Kinetic parameters of IL-1 alpha-induced hemorrhage were similar to those observed with recombinant murine TNF-alpha (TNF-alpha) or LPS in RIF-1 fibrosarcomas in C3H/HeN (endotoxin-sensitive) mice. However, the amount of TNF found in the sera or tumors of animals treated with LPS was more than 20-fold higher than in mice treated with IL-1 alpha, and LPS induced similar degrees of hemorrhagic necrosis, which was measured by determining the packed volume of red blood cells by 59Fe labeling. A low but significantly hemorrhagic dose of IL-1 alpha induced no detectable TNF in tumors. Pretreatment with 250 micrograms of neutralizing antibody to TNF had no effect on IL-1 alpha-induced hemorrhage, whereas TNF-alpha- and LPS-induced hemorrhagic effects were significantly reduced. These results demonstrate an important antitumor activity of IL-1 alpha that appears to be independent of TNF.

Animals↗
PubMed2005

Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis.

Levels of soluble tumour necrosis factor receptors (sTNFRs) are elevated in the circulation of patients with rheumatoid arthritis (RA). Although these receptors can act as natural inhibitors of tumour necrosis factor-alpha, levels of sTNFRs in RA appear to be insufficient to prevent tumour necrosis factor-alpha induced inflammation. The factors that regulate circulating levels of sTNFRs are unclear, but polymorphisms in the tumour necrosis factor receptor genes may play a role. We investigated the relationship between polymorphisms in the tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) genes and levels of sTNFRs in two groups of Caucasian RA patients: one with early (disease duration < or = 2 years; n = 103) and one with established disease (disease duration > or = 5 years; n = 151). PCR restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNF-RI gene and the T676G polymorphism in TNF-RII. Levels of sTNFRs were measured using ELISA. We also isolated T cells from peripheral blood of 58 patients with established RA with known TNF-R genotypes, and release of sTNFRs into the culture medium was measured in cells incubated with or without phytohaemagglutinin. Serum levels of the two sTNFRs (sTNF-RI and sTNF-RII) were positively correlated in both populations, and the level of each sTNFR was significantly higher in the patients with established disease (P < 0.0001). Multiple regression analyses corrected for age, sex and disease duration revealed a significant trend toward decreasing sTNF-RI and sTNF-RII levels across the TNF-RII genotypes (TT > TG > GG) of patients with established disease (P for trend = 0.01 and P for trend = 0.03, respectively). A similar nonsignificant trend was seen for early disease. No relationship with the TNF-RI A36G polymorphism was observed. sTNFRs released by isolated T cells exhibited a similar trend toward decreasing levels according to TNF-RII genotype, although only the association with levels of sTNF-RII was significant. Strong correlations were found between levels of circulating sTNFRs and levels released by T cells in vitro. Our data indicate that the T676G polymorphism in TNF-RII is associated with levels of sTNFRs released from peripheral blood T cells, and with circulating levels of sTNFR in patients with RA.

Arthritis, Rheumatoid↗
PubMed1990

Subcutaneous perfusion of tumor necrosis factor induces local proliferation of fibroblasts, capillaries, and epidermal cells, or massive tissue necrosis.

Mouse recombinant tumor necrosis factor (TNF) (or its solvent alone as a control) was administered subcutaneously to mice by a cannula connected to an osmotic minipump. Perfusion at a rate of 35 ng/hr for seven days induced the formation of a tissue mass composed mainly of fibroblasts, collagen, and capillaries. Necrosis (apoptosis) of isolated fibroblasts was observed. Polymorphonuclear leukocytes were abundant after three to four days of perfusion but were absent later. The covering epidermis showed a hyperplastic reaction associated with necrosis of isolated keratinocytes. Perfusion at a rate of 170 ng/hr led, after four to five days, to a massive necrosis. Necrosis was completely prevented by rabbit anti-TNF IgG but not by anti-LPS IgG, irradiation, or administration of indomethacin.

Animals↗
PubMed1998

Selective induction of tumor necrosis factor receptor type II gene expression by tumor necrosis factor-alpha in C6 glioma cells.

Using reverse transcription-polymerase chain reaction (RT-PCR) technique, the levels of tumor necrosis factor receptors gene expression in C6 glioma cells upon induction with tumor necrosis factor-alpha (TNF-alpha) were analysed. In control cells, the level of mRNA for tumor necrosis factor receptor type II (TNF-R2; 75/80 kDa) was much lower than that of tumor necrosis factor receptor type I (TNF-R1; 55/60 kDa). Upon exposure to TNF-alpha, the TNF-R2 mRNA level was greatly increased, while the TNF-R1 mRNA level remained unchanged even after 48 h. The induction of TNF-R2 gene expression by TNF-alpha was dose-dependent and seemed to be unique to TNF-alpha, as IL-6 had no effect. Since TNF-R2 was reported to mediate mitogenic effect in many other cell types, it is likely that the reported proliferative effect of TNF-alpha on astrocytes and C6 glioma cells was mediated by this TNF receptor subtype.

Actins↗
PubMed1999

Fatal granuloma necrosis without exacerbated mycobacterial growth in tumor necrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium.

The pathogenesis of mycobacterial infections is associated with the formation of granulomas in which both antibacterial protection and tissue damage take place concomitantly. We used murine Mycobacterium avium infection to compare the development of granulomatous lesions in intravenously infected tumor necrosis factor receptor p55 (TNFRp55) gene-deficient (p55(-/-)) mice to the development of granulomatous lesions in M. avium-infected syngeneic C57BL/6 (p55(+/+)) mice. Up to 5 weeks after infection with either the highly virulent M. avium strain TMC724 or the intermediately virulent M. avium strain SE01, bacterial counts in the liver, spleen, and lung of p55(-/-) mice were identical to or lower than those in infected p55(+/+) mice. However, the formation of mononuclear cell foci in the liver was delayed by approximately 2 to 3 weeks in p55(-/-) mice compared to the results obtained for infected p55(+/+) mice. Despite comparable bacterial loads, granulomas in p55(-/-) mice underwent progressive necrosis, causing damage to the surrounding liver tissue. The appearance of necrotizing granulomas was associated with the death of all infected p55(-/-) mice, regardless of the virulence of the M. avium strain used for infection. Granulomatous lesions in the liver contained three times as many CD3(+) cells in p55(-/-) mice yet appeared more diffuse than in p55(+/+) mice. Semiquantitative reverse transcription-PCR studies revealed that prior to mouse death, interleukin-12 (IL-12) and gamma interferon mRNA levels were up regulated in the livers of infected p55(-/-) mice, while mRNA levels for tumor necrosis factor, the inducible isoform of nitric-oxide synthase (iNOS), and IL-10 were similar to those found in infected p55(+/+) mice. In response to persistent mycobacterial infection, the absence of TNFRp55 causes the disregulation of T-cell-macrophage interactions and results in fatal granuloma necrosis even when adequate antibacterial functions are maintained.

Animals↗
PubMed1996

Evidence that the initial up-regulation of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response that prevents cholesterol-induced cellular necrosis. Proposed role of an eventual failure of this response in foam cell necrosis in advanced atherosclerosis.

Macrophages in atherosclerotic lesions accumulate free cholesterol (FC) as well as cholesteryl ester and appear to have high rates of phospholipid (PL) synthesis and increased PL mass. Previous short term (i.e. </=24 h) studies with cultured macrophages have shown that these cells respond to FC loading by up-regulating phosphatidylcholine biosynthesis. We propose that this response is adaptive by keeping the FC:PL ratio in the macrophages from reaching toxic levels. We further propose that one cause of macrophage necrosis, a prominent and important event in atherosclerosis, is an eventual decrease of this adaptive response. To explore these ideas, cultured macrophages were loaded with FC for up to 4 days and assayed for phosphatidylcholine biosynthesis, FC and PL mass, and cytotoxicity. For the first 24 h, cellular phosphatidylcholine biosynthesis and FC and PL mass increased 3-4-fold, and thus the FC:PL molar ratio was prevented from reaching very high levels; at this point, there were no overt signs of cytotoxicity. Over the next 24-48 h, however, phosphatidylcholine biosynthesis, and then phosphatidylcholine mass, began to decrease. Initially, the macrophages remained healthy and continued to accumulate FC, but eventually these macrophages, but not unloaded macrophages, became necrotic (swollen organelles and disrupted membranes). Lipoprotein dose studies indicated a close relationship between the onset of macrophage necrosis and the FC:PL ratio. To test further the causal nature of these relationships, cellular FC and PL mass were independently manipulated by using high density lipoprotein3 (HDL3) to decrease cellular FC and choline depletion to decrease cellular PC. As predicted by our hypotheses, HDL3 protected FC-loaded macrophages from necrosis, whereas choline depletion accelerated cytotoxic changes. These findings support the idea that the initial increase in phosphatidylcholine biosynthesis in FC-loaded macrophages is an adaptive response that prevents cholesterol-induced macrophage necrosis. We propose that an eventual failure of the PL response in foam cells may represent one cause of macrophage necrosis in advanced atherosclerotic lesions.

Arteriosclerosis↗
PubMed2002

Arsenic induces tumor necrosis factor alpha release and tumor necrosis factor receptor 1 signaling in T helper cell apoptosis.

Long-term exposure to arsenic induces arsenical cancers in human beings. Arsenic has been shown to induce apoptosis in a variety of cell systems. Previous studies revealed that patients with arsenic-induced Bowen's disease showed a defective cell-mediated immunity and decreased percentages of T cell and T helper cell subpopulations in peripheral mononuclear cells. The purpose of this study was to investigate the effects of arsenic on T cell survival and function in mononuclear cells. Arsenic concentrations higher than 1 micro M induced tumor necrosis factor alpha release from mononuclear cells and caused a cytotoxic effect on T cells. When exposed to higher concentrations of arsenic, apoptosis was induced. CD4+ cells were the major apoptoic population in mononuclear cells. Tumor necrosis factor receptor 1 expression on CD4+ cells, but not Fas/FasL, was significantly enhanced by arsenic treatment compared to other mononuclear cells. Increased expressions of tumor necrosis factor receptor 1 related death domain proteins and activated caspases were observed. These findings indicate that tumor necrosis factor receptor 1 signaling is the major pathway in arsenic-induced T helper cell apoptosis.

Adult↗
PubMed1987

Relationship of tumour necrosis factor and endotoxin to macrophage cytotoxicity, haemorrhagic necrosis and lethal shock.

In this communication we discuss preliminary evidence suggesting a very strong synergism between tumour necrosis factor (TNF) and lipopolysaccharide (LPS) or between TNF and other bacteria in causing haemorrhagic necrosis and lethal shock. We found that TNF by itself does not cause haemorrhagic necrosis when injected into normal skin. TNF also had a rather low systemic toxicity when injected into disease-free, germfree-derived, defined-flora animals. On the other hand the addition of small amounts of LPS markedly raised the lethality of intravenous TNF treatments, and LPS injected into normal skin 'prepared' the site of injection for subsequent induction of haemorrhagic necrosis by locally injected TNF. Similar synergism was observed between TNF and mycoplasma. We suggest that the synergism between TNF and bacterial endotoxin (or other bacteria or bacterial products) may be part of an important defence mechanism against infections which is independent of specific immunity mediated by B and T cells. This synergism may be useful in increasing the therapeutic effects of TNF on tumours if the development of systemic toxicity in this treatment can be prevented.

Animals↗
PubMed1994

Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNF alpha).

Twenty-seven patients treated with high-dose rTNF alpha, IFN gamma and melphalan by isolated limb perfusion were histologically documented. There were 20 cases of melanoma-in-transit metastases and 7 cases of high-grade soft-tissue sarcoma. Biopsies were taken before IFN gamma, after IFN gamma, before TNF alpha and between 2 hr and 60 days after the TNF alpha perfusion. Immunohistochemistry was performed for adhesion molecules ICAM-I, ELAM-I (E selectin), VCAM-I and PECAM. During the first hours after beginning perfusion, the endothelial cells of the tumour capillaries appeared swollen. Significant tumour necrosis was already observed 3 hours after the perfusion in melanoma cases. The overall predominant feature was coagulative necrosis associated or not with haemorrhagic necrosis. TNF alpha induced increased expression of ELAM-I and VCAM-I adhesion molecules on intratumoral endothelial cells. The activated tumour vessels were progressively destroyed. Significant intravascular recruitment of polymorphonuclear cells (PMNs) was observed 3 hr after starting TNF alpha; it was followed by diapedesis and tumour colonization 3 days later. T lymphocytes and macrophages were detected during the first 7 days and B lymphocytes during the second week. Melanoma in transit metastases treated with alkylating agent alone did not show significant necrosis and did not express high levels of adhesion molecules (ELAM-I, VCAM-I) nor infiltration by PMN.

Cell Adhesion Molecules↗
PubMed2002

Tumor necrosis factor alpha increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase- and NF-kappaB-dependent mechanism.

Acid sphingomyelinase (ASMase) and NF-kappaB participate in tumor necrosis factor alpha (TNFalpha) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-kappaB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-kappaB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFalpha. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-kappaB p50. We conclude that TNFalpha can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-kappaB-dependent mechanism. TNFalpha levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFalpha signal transduction will diminish neuronal necrosis in these diseases.

Animals↗
PubMed1998

Apoptosis precedes necrosis of fish cell line with infectious pancreatic necrosis virus infection.

The current view of infectious pancreatic necrosis virus (IPNV) infection includes a necrotic process that relies primarily on the histological appearance of tissue after the degenerative process. We tested this view by examining the possibility that apoptosis is a component of double-stranded RNA virus (IPNV) that induces fish embryonic cell death. Four kinds of assays for apoptosis were used in analyzing IPNV-infected CHSE-214 cells: (1) assay with terminal deoxynucleotidyl transferase (TdT)-mediated end-labeling of DNA in nuclei of intact cells during virus infection, (2) assay for procoagulant activity, (3) assay for DNA ladders, and (4) electron microscopic assays for the ultrastructural changes in characteristic apoptotic cells. In all p.i. samples, both low and high m.o.i. groups contained apoptotic nuclei, according to TdT-mediated dUTP labeling of intact cells, but in control CHSE-214 cells, apoptotic nuclei were rare at all levels of incubation sampled by TdT-mediated dUTP labeling. Prenecrotic or postnecrotic cells were found to express phosphatidylserine on the surface by annexin V-FITC labeling, but normal cells did not. DNAs from both 4 h p.i. of high m.o.i. and 8 h p.i. of low m.o.i. were found to be cleaved into fragments indicative of preferential cleavage at internucleosomal sites. The IPNV-infected CHSE-214 cells were analyzed with an electron microscope and showed a pattern of ultrastructural change, indicating that apoptosis appears before pathological changes of necrosis, including condensed chromatin, fragmented nuclei, nuclei with chromatin marginations, and secondary necrosis from prenecrotic cells in IPNV-infected CHSE-214 cells. Together, these findings show that apoptosis precedes any detectable necrotic change in CHSE-214 cells that is currently viewed as necrosis. Thus, apoptosis characterizes the onset of pathology in host cells and is followed by necrotic processes.

Animals↗
PubMed1991

Induction of inflammatory cell infiltration and necrosis in normal mouse skin by the combined treatment of tumor necrosis factor and lithium chloride.

Previously we reported that lithium chloride (LiCl) potentiates tumor necrosis factor (TNF)-mediated cytotoxicity in vitro and in vivo. Here, using a murine normal skin model, it is shown that a subcutaneous injection of TNF plus LiCl induces acute dermal and subcutaneous inflammation and necrosis. Histology showed a marked initial dermal and subcutaneous neutrophil infiltrate by approximately 2 hours, followed by a predominantly mononuclear infiltrate by 24 hours, which remained present for several days. Tumor necrosis factor or LiCl alone induced negligible inflammation, disappearing after 6 hours; furthermore there was never necrosis or ulceration of the overlying skin in case of single-agent application. In vitro studies showed that the combination of TNF and LiCl, but not either agent alone, was directly cytotoxic to fibroblastic cells of murine skin. No inflammatory infiltration was visible in tumors treated intratumorally or perilesionally with TNF plus LiCl, although the latter treatment resulted in a perilesional leukocyte infiltration. Furthermore the combination of TNF and LiCl had no effect on macrophage cytotoxicity to L929 tumors.

Animals↗
PubMed1994

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma.

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.

Adult↗