Inducer-Specific Bidirectional Regulation by Thalidomide and Phenylphthalimides of Tumor Necrosis Factor-α Production

Miyachi, Hiroyuki; Azuma, Arata; Hioki, Erika; Iwasaki, Shigeo; Kobayashi, Yoshiro; Hashimoto, Yuichi

doi:10.1006/bbrc.1996.1043

Cited by 37 publications

(19 citation statements)

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“…Thalidomide is noted for its inhibition of TNF-α production by LPS-activated human blood monocytes in culture (Sampaio et al, 1991), but bi-directional dose-dependent TNF-α modulation has been reported, depending on the cell type and stimulator used. Thalidomide enhanced TNF-α synthesis by the HL-60 human leukaemia cell line induced with phorbol esters, but inhibited TNF-α synthesis induced with okadaic acid in the same cell line (Miyachi et al, 1996). While thalidomide inhibited synthesis of TNF-α in LPS-stimulated cultures of unfractionated human blood mononuclear cells, it enhanced TNF-α synthesis in cultures of THP-1 cells and in the adherent population of human blood mononuclear cells (Shannon and Sandoval, 1996).…”

Section: Discussionmentioning

confidence: 94%

Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid

Cao

et al. 1999

Br J Cancer

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Summary 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), synthesized in this laboratory and currently in phase I clinical trial, is a low molecular weight inducer of tumour necrosis factor-α (TNF-α). Administration of DMXAA to mice with established transplantable tumours elicits rapid vascular collapse selectively in the tumour, followed by extensive haemorrhagic necrosis mediated primarily through the production of TNF-α. In this report we have investigated the synthesis of TNF-α mRNA in hepatic, splenic and tumour tissue. Coadministration of thalidomide with DMXAA increased anti-tumour activity and increased intra-tumoural TNF-α production approximately tenfold over that obtained with DMXAA alone. Thalidomide increased splenic TNF-α production slightly but significantly decreased serum and hepatic levels of TNF-α induced with DMXAA. Lipopolysaccharide (LPS) induced 300-fold higher serum TNF-α than did DMXAA at the maximum tolerated dose, but induced similar amounts of TNF-α in spleen, liver and tumour. Splenic TNF-α activity induced with LPS was slightly increased with thalidomide, but serum and liver TNF-α levels were suppressed. Thalidomide did not increase intra-tumoural TNF-α production induced with LPS, in sharp contrast to that obtained with DMXAA. While thalidomide improved the anti-tumour response to DMXAA, it had no effect on the anti-tumour action of LPS that did not induce a significant growth delay or cures against the Colon 38 tumour. The increase in the anti-tumour action by thalidomide in combination with DMXAA corresponded to an increase in intra-tumoural TNF-α production. Co-administration of thalidomide may represent a novel approach to improving selective intra-tumoural TNF-α production and anti-tumour efficacy of DMXAA.Keywords: DMXAA; thalidomide; Colon 38; endotoxin; tumour necrosis factor 716British Journal of Cancer (1999) 80(5/6), 716-723 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 30 Silva et al, 1994), but was withdrawn from use as a sedative and anti-emetic in the 1960s because of its teratogenicity (Fabro et al, 1967). Recent studies indicate that its immunosuppressive and anti-inflammatory effects would be beneficial to the treatment of graft-versus-host disease (Vogelsang et al, 1992;Uthoff et al, 1995), rheumatoid arthritis (Gutierrez-Rodriguez et al, 1989), prevention of graft rejection (Vogelsang et al, 1988;Uthoff et al, 1995), HIV/AIDS (Makonkawkeyoon et al, 1993;Moreira et al, 1997), sarcoidosis (Carlesimo et al, 1995) and various other inflammatory diseases (Burroughs et al, 1995). In experiments to determine whether suppression of serum TNF-α production by thalidomide affected the antitumour response to DMXAA, we found that, while serum TNF-α levels decreased, anti-tumour activity was unexpectedly improved . Reduction of tumour blood flow induced by DMXAA, which is thought to be mediated by TNF-α, was not reversed by thalidomide . Thalidomide analogues that were more potent than thalidomide in inhibiting DMXAA-induced serum TNF-α were also more potent in...

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Section: Discussionmentioning

confidence: 94%

Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid

Cao

et al. 1999

Br J Cancer

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“…Furthermore, it was suggested that THD has a potential for the treatment of several immune disorders and diseases related to elevated TNF-levels (chronic graft-versus-host disease, oral and oropharyngeal ulcers associated with HIV infection, erythema nodosum leprosum in leprosy, and other inflammatory skin diseases) since it has an inhibitory effect on TNF production by enhancing TNF-mRNA degradation (Moreira et al 1993). There are other studies, however, which have reported an enhancement of TNF production by THD in MonoMac 6 cell lines and HL60 cells (Miyachi et al 1996;Förster et al 1995). For monocyte and PMNL phagocytosis, a bimodal dose-activity relationship is reported with enhanced (1 µg/ml) and reduced (10 µg/ml) phagocytic activity (Doll et al 1983), whereas respiratory burst activity remained unaffected in various in vitro assays .…”

Section: Introductionmentioning

confidence: 84%

Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium

Dunzendorfer¹,

Schratzberger²,

Reinisch³

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Vascular endothelium activated by endotoxin and cytokines plays an important role in organ inflammation and blood leukocyte recruitment. Neutrophils, which are a homogeneous population of effector cells, are rapidly attracted in large numbers to sites of inflammation where they form an early response to infection or injury. Excessive production of various interleukins, TNF, arachidonic acid metabolites, and other substances by neutrophils and macrophages results in systemic endothelial cell injury, a fundamental problem. In the present study, we investigated in vitro the effects of thalidomide (THD) on activation of endothelial cells for enhanced transmigration of neutrophils by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF), and interleukin-1 (IL-1). Modulation of endotoxin- and cytokine-induced neutrophil chemotaxis and respiratory burst by THD were also studied. Treatment of HUVEC with THD in combination with LPS, TNF, and IL-1, respectively, antagonized LPS-activated transmigration of neutrophils but stimulated the effects of TNF and IL-1. All of the agents used-THD, LPS, TNF, and IL-1-inhibited neutrophil chemotaxis. Addition of THD to the neutrophils had no effect on LPS-inhibited chemotaxis whereas the TNF- and IL-1-induced chemotaxis was modulated in a bimodal manner. However, THD failed to influence neutrophil respiratory burst activity. Results demonstrate that THD differentially affects mediator-induced activation of HUVEC and neutrophils.

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“…This negative effect was related to a paradoxical enhancement of TNF-α production since increased serum TNF-α levels have been observed in TEN patients treated with thalidomide [104]. Recent data have demonstrated that thalidomide may exert bidirectional dose-dependent effects on TNF-α production, depending on the cell type and the method of cellular activation [105, 106]. Thus, under certain experimental designs, TNF-α production is significantly enhanced by thalidomide in vitro at a concentration achieved in vivo.…”

Section: Ten Treatmentsmentioning

confidence: 99%

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Paquet

Pierard

Quatresooz³

2005

Int Arch Allergy Immunol

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Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-α (TNF-α) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-α antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.

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Inducer-Specific Bidirectional Regulation by Thalidomide and Phenylphthalimides of Tumor Necrosis Factor-α Production

Cited by 37 publications

References 0 publications

Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid

Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid

Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

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