scholarly journals The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity.

1988 ◽  
Vol 167 (3) ◽  
pp. 1067-1085 ◽  
Author(s):  
E A Havell ◽  
W Fiers ◽  
R J North
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Regression ◽  
Cytotoxic Action ◽  
Complete Regression ◽  
Severe Toxicity ◽  
Hemorrhagic Necrosis ◽  
Necrosis Factor

The ability of murine recombinant tumor necrosis factor (rTNF) and natural TNF in tumor-necrotizing serum (TNS) to cause regression of the SA1 sarcoma was investigated. We found that to cause regression of a 9-d SA1 sarcoma, near lethal quantities of rTNF and TNS had to be given to the host. However, even at these highly toxic doses, rTNF was not reliable at causing complete tumor regression. On the other hand, both types of TNF were reliable at causing a tumor hemorrhagic reaction that resulted in the destruction of greater than 75% of the tumor's center in 24 h. The TNF-induced hemorrhagic reaction involved the development of numerous petechial hemorrhages in the tumor's vascular bed, which apparently resulted from destruction of the tumor's blood vessels. It was possible to follow the development of the hemorrhagic reaction against time after giving rTNF or TNS by measuring the intratumor extravasation of 51Cr-labeled syngeneic red cells. According to this method, TNF-induced intratumor hemorrhaging was in progress within 1 h of giving TNF and continued for about a 6-h period. However, the hemorrhagic reaction was greatly reduced and complete regression of the rim of the living tumor tissue that survived hemorrhagic necrosis failed to occur, if SA1 sarcoma was growing in T cell-deficient (TXB) mice. This indicates that the TNF-induced hemorrhagic reaction is partly dependent, and the tumor regression that follows is completely dependent on host immunocompetence. This suggests in turn, that rTNF does not directly destroy SA1 tumor cells in vivo, even though it was shown that it can destroy SA1 tumor cells in vitro. This interpretation is supported by the additional findings that rTNF was no more therapeutic against a 3-d (3-mm) SA1 than against a 9-d (8-mm) SA1, and was no more therapeutic when injected directly into the tumor than when injected intravenously. Lastly it was possible to completely inhibit the ability of rTNF and TNS to cause tumor hemorrhagic necrosis and regression by infusing the host with a monospecific, polyvalent anti-rTNF antibody that neutralized the cytotoxic action of rTNF in vitro.

scholarly journals Nonhematopoietic cells selected for resistance to tumor necrosis factor produce tumor necrosis factor.

1986 ◽  
Vol 164 (4) ◽  
pp. 1350-1355 ◽  
Author(s):  
B Y Rubin ◽  
S L Anderson ◽  
S A Sullivan ◽  
B D Williamson ◽  
E A Carswell ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cytotoxic Action ◽  
Surface Receptors ◽  
L Cells ◽  
Produce Tumor Necrosis Factor ◽  
Hemorrhagic Necrosis ◽  
Resistant Lines ◽  
Mouse Sarcoma ◽  
Necrosis Factor

TNF-resistant lines of L cells can be derived from TNF-sensitive populations by repeated exposure to TNF, and these resistant L cells, in contrast to sensitive L cells and other types of cells, lack demonstrable cell surface receptors for TNF. We have now found that TNF-resistant L cells produce a factor that is cytotoxic for L cells and has the following distinguishing characteristics of mouse TNF: it is a protein of 43 kD, composed of 16 kD subunits, that competes with TNF for receptor binding, induces hemorrhagic necrosis of the TNF-sensitive mouse sarcoma Meth A, has synergistic cytotoxic action with interferon, and its activity is neutralized by antibody to TNF. The two conclusions of this study are that cells selected for TNF resistance spontaneously produce a molecule resembling macrophage TNF, and that cells of nonhematopoietic origin are capable of producing TNF.

scholarly journals The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity.

1978 ◽  
Vol 148 (6) ◽  
pp. 1560-1569 ◽  
Author(s):  
M J Berendt ◽  
R J North ◽  
D P Kirstein
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Immunity ◽  
Tumor Necrosis ◽  
Temporal Relationship ◽  
Tumor Regression ◽  
Effector T Cells ◽  
Hemorrhagic Necrosis ◽  
Concomitant Immunity ◽  
Necrosis Factor

It was shown that of four syngeneic, murine tumors investigated, only those that evoked the generation of a state of concomitant anti-tumor immunity were susceptible to endotoxin-induced regression. Moreover, the temporal relationship between the generation of concomitant immunity and the onset of susceptibility to endotoxin-induced regression points to the likely possibility that tumor regression depends on the preceding acquisition of the specifically-sensitized, effector T cells that express concomitant immunity. It is suggested that endotoxin-induced hemorrhagic necrosis which invariably precedes tumor regression serves to create conditions inside the tumor that are conducive to the entry and the functioning of effector T cells. It is also suggested that tumor necrosis factor causes hemorrhagic necrosis rather than tumor regression.

scholarly journals Glucocorticoid-mediated inhibition of endotoxin-induced intratumor tumor necrosis factor production and tumor hemorrhagic necrosis and regression.

1989 ◽  
Vol 170 (3) ◽  
pp. 703-710 ◽  
Author(s):  
R J North ◽  
E A Havell
Keyword(s):  
Tumor Necrosis Factor ◽  
Intravenous Injection ◽  
Subcutaneous Injection ◽  
Tumor Necrosis ◽  
Complete Regression ◽  
Tumor Necrosis Factor Production ◽  
The Core ◽  
Hemorrhagic Necrosis ◽  
Extensive Necrosis ◽  
Necrosis Factor

Intravenous injection of 25 micrograms of bacterial endotoxin on day 9 of growth of the SA1 sarcoma results in extensive necrosis of the core of this tumor and in its subsequent complete regression. Tumor hemorrhagic necrosis and regression failed to occur in mice that were given a subcutaneous injection of cortisone acetate or dexamethasone 12 h before being giving endotoxin. Inhibition of tumor hemorrhagic necrosis and regression by glucocorticoids was associated with inhibition of endotoxin-induced intratumor TNF production that normally takes place several h after endotoxin is given. In contrast, glucocorticoids had no effect on the ability of intravenously injected rTNF to cause tumor hemorrhagic necrosis and regression. The results lend further support to the belief that TNF is the predominant mediator of endotoxin-induced hemorrhagic necrosis of established murine tumors, and that hemorrhagic necrosis is a prerequisite for the immunologically mediated regression that follows.

scholarly journals Growth inhibitory and cytotoxic action of rabbit tumor necrosis factor against bovine capillary endothelial cells in vitro.

1985 ◽  
Vol 61 (10) ◽  
pp. 471-474 ◽  
Author(s):  
Noboru SATO ◽  
Yoshio SAWASAKI ◽  
Katsuyuki HARANAKA ◽  
Nobuko SATOMI ◽  
Hideo NARIUCHI ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cytotoxic Action ◽  
Growth Inhibitory ◽  
Capillary Endothelial Cells ◽  
Necrosis Factor

scholarly journals Enhancement of experimental metastasis by tumor necrosis factor.

1993 ◽  
Vol 177 (5) ◽  
pp. 1391-1398 ◽  
Author(s):  
P Orosz ◽  
B Echtenacher ◽  
W Falk ◽  
J Rüschoff ◽  
D Weber ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Nucleolar Organizer ◽  
Metastatic Potential ◽  
Nucleolar Organizer Regions ◽  
Tumor Bearing ◽  
Necrosis Factor

The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.

Lack of Cell-Cycle Specific Effects of Tumor Necrosis Factor-αon Tumor Cells In Vitro: Implications for Combination Tumor Therapy with Doxorubicin

2002 ◽  
Vol 20 (4) ◽  
pp. 499-508 ◽  
Author(s):  
Alexander H. van der Veen ◽  
Timo L. M. ten Hagen ◽  
Ann L. B. Seynhaeve ◽  
Alexander M. M. Eggermont
Keyword(s):  
Cell Cycle ◽  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Therapy ◽  
Specific Effects ◽  
Necrosis Factor

scholarly journals Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes.

1991 ◽  
Vol 173 (3) ◽  
pp. 647-658 ◽  
Author(s):  
R J Barth ◽  
J J Mulé ◽  
P J Spiess ◽  
S A Rosenberg
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Interferon Gamma ◽  
Mechanism Of Action ◽  
Tumor Necrosis ◽  
Tumor Infiltrating Lymphocytes ◽  
Ifn Gamma ◽  
Infiltrating Lymphocytes ◽  
Necrosis Factor

We have investigated the mechanisms whereby adoptively transferred murine CD8+ lymphocytes mediate tumor regressions. Noncytolytic, CD8+ tumor-infiltrating lymphocytes (TIL) eradicated established lung tumors in irradiated mice. Many cytolytic and noncytolytic CD8+ TIL cultures specifically secreted interferon gamma (IFN-gamma) and tumor necrosis factor when stimulated with tumor cells in vitro. The effectiveness of TIL when adoptively transferred to mice bearing micrometastases correlated better with their ability to specifically secrete lymphokines than with their cytotoxicity in vitro. In 14 of 15 tests, therapeutically effective TIL specifically secreted IFN-gamma in vitro, whereas only 1 of 11 ineffective TIL specifically secreted IFN-gamma. In contrast, only 8 of 15 therapeutically effective TIL were cytolytic. Antibodies to TNF inhibited the effectiveness of two adoptively transferred TIL cultures. In five experiments, antibodies to IFN-gamma abrogated the ability of four different CD8+ TIL cultures to mediate tumor regressions, indicating that secretion of IFN-gamma is an essential part of the mechanism of action of TIL.

Tumor Necrosis Factor in the Pathogenesis of Human Diseases

1992 ◽  
Vol 5 (2) ◽  
pp. 131-134
Author(s):  
P. Ghezzi
Keyword(s):  
New York ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Biological Activities ◽  
Laboratory Animals ◽  
Hemorrhagic Necrosis ◽  
Necrosis Factor

This paper will deal with the role of tumor necrosis factor (TNF) in the pathogenesis of various diseases. However, it will be important to remember that originally TNF was characterized as an antitumor factor. In fact, it was known that endotoxin was able to induce hemorrhagic necrosis of some tumors in mice. In 1975 Carswell et al. demonstrated the presence of a tumor necrotizing activity (termed “tumor necrosis serum”) in the sera of mice primed with C. parvum or BCG, and subsequently injected with endotoxin (1). Later it was found that this factor was a macrophage product and was termed TNF. In vivo TNF induced hemorrhagic necrosis of Meth A sarcoma and in vitro demonstrated cytotoxic activity against various tumor cell lines (2). In 1984, TNF was purified and its cDNA was cloned, and the production of substantial amounts of recombinant TNF allowed the characterization of its various biological activities (3). In parallel to these studies on tumor necrosis, the group of Cerami, at the Rockefeller University in New York was studying the mechanisms of cachexia and wasting associated with infection. They found that infection or injection of endotoxin in laboratory animals resulted in a marked hypertrygliceridemia, which was associated with an inhibition of lipoprotein lipase. They hypothesized that a host-derived mediator was responsible for this and other metabolic derangements observed in infection. This factor, which was termed “cachectin”, was later found to be produced by macrophages, and once it was purified and sequenced it became clear that TNF and cachectin were identical (4).

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