Tumor necrosis factor activities and cancer therapy — A perspective

Sidhu, Rajinder S.; Bollon, Arthur P.

doi:10.1016/0163-7258(93)90037-e

Cited by 101 publications

(73 citation statements)

References 403 publications

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“…TNF-a is known to exhibit a multitude of different effects upon binding to two distinct high-affinity receptors, TNF-R1 and TNF-R2 (Tartaglia and Goeddel, 1992;Sidhu and Bollon, 1993), the specific functional impact of each receptor type on growth regulation and cytotoxicity still being under discussion (Heller et al, 1992;Tartaglia et al, 1993;Grell et al, 1993;Higuchi and Aggarwal, 1994). In our tumour model, however, the antiproliferative effect of TNF-a was exclusively mediated by TNF-R1 since no TNF-R2 mRNA was detectable.…”

Section: Expression Of Tnf-rj and Tnf-r2mentioning

confidence: 99%

“…TNF-a is known to be a pleiotropic cytokine, capable of eliciting a wide variety of biological responses, which are mediated by two different receptors, TNF-R1 and TNF-R2 of 55 kDa and 75 kDa respectively (Tartaglia and Goeddel, 1992;Sidhu and Bollon, 1993). Among these biological effects, cytotoxic and cytostatic effects on diverse malignant cell lines in vitro (Sugarman et al, 1985;Rutka et al, 1988;Pusztai et al, 1993;Beyaert and Fiers, 1994) suggested a possible clinical use for TNF-oa either alone or in combination with other compounds.…”

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confidence: 99%

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Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

Engers

Roy²,

Heymer³

et al. 1996

Br J Cancer

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Epithelioid sarcoma is a highly malignant soft tissue tumour that is refractory to conventional chemotherapy and irradiation. Since permanent cell lines of this tumour are extremely rare, in vitro data on compounds with significant antiproliferative effects are still lacking. Therefore, we investigated the effects of retinoic acid (RA) and tumour necrosis factor alpha (TNF-alpha) on tumour cell proliferation of three different clonal subpopulations (GRU-1A, GRU-1B, GRU-1C) derived from the same human epithelioid sarcoma cell line, GRU-1. In GRU-1A both RA (P=0.01) and TNF-alpha (P=0.002) exhibited highly significant and dose-dependent growth inhibitory effects, which could further be increased by a combined application of both compounds (P<0.006). GRU-1B proved to be sensitive to RA (P=0.006), whereas no response to TNF-alpha was observed. GRU-1C was resistant to both RA and TNF-alpha. The antiproliferative effect of TNF-alpha was mediated by TNF receptor 1(TNF-R1) and correlated positively with both the number of TNF-R1 per cell and receptor affinity. No correlation was detected between RA-induced growth inhibition and the expression pattern of the RA receptors (RARs) RAR-alpha, RAR-beta, and RAR-gamma. Plating efficiency, however, could exclusively be reduced by RA in GRU-1B, the only cell line expressing RAR-alpha. Taken together, these data are the first showing significant antiproliferative effects in human epithelioid sarcoma by RA and TNF-alpha. Whereas the TNF-alpha response seems to depend on the expression of TNF-R1, no simple correlation could be found between RA sensitivity and the expression pattern of RARs. Images Figure 1 Figure 3

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Section: Expression Of Tnf-rj and Tnf-r2mentioning

confidence: 99%

mentioning

confidence: 99%

Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

Engers

Roy²,

Heymer³

et al. 1996

Br J Cancer

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“…Although incidental clinical reports on IHP have confirmed its potential use in humans (Aigner, 1988; Skibba, 1988;Hafstrom, 1994), it is clear that optimization of the IHP methodology is needed. In addition, a drug(s) that would provide optimal anti-tumour activity in the IHP setting is at present unknown.High-dose tumour necrosis factor alpha (TNF-a) has been shown to be highly tumoricidal both in vitro and in vivo (Alexander, 1991; Jiiattelai, 1991;Sidhu, 1993). Many phase I and II studies have demonstrated that systemic administration of TNFax in man results in considerable dose-limiting toxicity at dose levels at which no anti-tumour activity is observed (Asher, 1987;Blick, 1987;Feinberg, 1988).…”

mentioning

confidence: 99%

“…High-dose tumour necrosis factor alpha (TNF-a) has been shown to be highly tumoricidal both in vitro and in vivo (Alexander, 1991; Jiiattelai, 1991;Sidhu, 1993). Many phase I and II studies have demonstrated that systemic administration of TNFax in man results in considerable dose-limiting toxicity at dose levels at which no anti-tumour activity is observed (Asher, 1987;Blick, 1987;Feinberg, 1988).…”

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confidence: 99%

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Rinkes

Vries²,

Jonker³

et al. 1997

Br J Cancer

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Summary Isolated limb perfusion with tumour necrosis factor alpha (TNF-a) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-a with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 ,ug kg-' TNF-ca (n = 5), (2) 50 9g kg-' TNF-a plus 1 mg kg-' melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-a levels of 5.1 ± 0.78 x 106 pg ml-(± s.e.m). Systemic leakage of TNF-a from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-a levels was observed in groups 1 and 2 with a median peak level of 23 ± 3 x 103 pg ml-' at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-a with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.Keywords: isolation; liver; perfusion; metastases; tumour necrosis factor The liver is the commonest site of dissemination in patients with colorectal cancer (Bengmark, 1969;Wagner, 1984;Strangl, 1994). Five-year survival rates of up to 35% have been reported for patients amenable for partial hepatic resection (Hughes, 1986;Scheele, 1990; Van Ooyen, 1992;Sugihara, 1993;Que, 1994). Unfortunately, the vast majority of colorectal metastases confined to the liver are considered to be unresectable (Greenway, 1988;Cady, 1991;Genari, 1992). In addition, systemic chemotherapy has so far failed to provide satisfactory results in these cases (Kemeny, 1983(Kemeny, , 1987. Therefore, it is mandatory to develop novel strategies to obtain tumour control in the liver.The concept of locoregional administration of chemotherapy is aimed at achieving high local concentrations while minimizing systemic drug levels in an attempt to reduce dose-limiting sideeffects. This might enhance anti-tumour efficacy as steep dose-response curves have been described for most chemotherapeutic agents (Frei, 1980;Canellos, 1987). Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994 (Kemeny, ...

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“…One experimental approach for improving the efficacy of mAb has been to fuse immunomodulatory molecules such as certain cytokines to therapeutic antibody using molecular biology techniques (5,6). These antibody fusion proteins seek to target immunostimulating properties of cytokine(s) into the tumor microenvironment, enhancing the positive effects of the therapy, but avoiding the adverse side effects observed after the systemic administration of some of those cytokines at high doses (7,8).…”

Section: Introductionmentioning

confidence: 99%

Decreased Survival of Human Breast Cancer Cells Expressing HER2/neuonIn vitroIncubation with an Anti-HER2/neuAntibody Fused to C5a or C5adesArg

Fuenmayor

Perez-Vazquez

Perez-Witzke

et al. 2010

Molecular Cancer Therapeutics

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Treatment of human epidermal growth factor receptor 2 (HER2/neu)-expressing breast cancer patients with a monoclonal antibody (mAb) directed against HER2/neu improves the outcome of chemotherapy. In cases in which remission is observed, antibody-dependent cell-mediated cytotoxicity (ADCC) seems to be one of the main mechanisms of anti-HER2/neu mAb action, implicating Fcγ receptors (FcγRs) in this tumoricidal activity. In vitro and in vivo studies have revealed that anti-HER2/neu-mediated ADCC is mainly accomplished by polymorphonuclear granulocytes (PMN). C5a, a cleavage product of the complement component C5, modulates FcγR expression via upregulation of activating and downregulation of inhibitory FcγRs. C5a also recruits PMNs to sites of inflammation and increases PMN survival. To enhance the recruitment and activation of C5a receptor-bearing cells into the tumor microenvironment, we developed antibody fusion proteins composed of a human IgG3 anti-HER2/neu antibody genetically fused to C5a [anti-HER2/neu IgG3-(C5a)] or to its derivative, C5a desArg [anti-HER2/neu IgG3-(C5a desArg )]. Both fusion proteins were expressed, properly assembled, and secreted by murine myeloma cells, and displayed chemotactic activity on human PMN. Under comparable conditions, anti-HER2/neu IgG3-(C5a desArg ) increased the survival of PMN more efficiently than anti-HER2/neu IgG3-(C5a) or C5a desArg . Surprisingly, incubation of the fusion proteins with breast cancer cells that overexpress HER2/neu (SK-BR-3) induced cell death at a dose at which the anti-HER2/neu IgG3 antibody was innocuous. In the presence of human peripheral blood leukocytes as effector cells, both fusion proteins induced tumor cell death more efficiently than anti-HER2/neu IgG3. These data suggest that anti-HER2/neu IgG3-(C5a) and anti-HER2/neu IgG3-(C5a desArg ) fusion proteins possess novel properties that could be useful in cancer immunotherapy. Mol Cancer Ther; 9(8); 2175-85. ©2010 AACR.

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Tumor necrosis factor activities and cancer therapy — A perspective

Cited by 101 publications

References 403 publications

Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Decreased Survival of Human Breast Cancer Cells Expressing HER2/neuonIn vitroIncubation with an Anti-HER2/neuAntibody Fused to C5a or C5adesArg

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