Tumour necrosis factor and cancer
Tumour necrosis factor (TNF) is a major inflammatory cytokine that was first identified for its ability to induce rapid haemorrhagic necrosis of experimental cancers. When efforts to harness this anti-tumour activity in cancer treatments were underway, a paradoxical tumour-promoting role of TNF became apparent. Now that links between inflammation and cancer are appreciated, is TNF a target or a therapeutic in malignant disease — or both?
Structure of tumour necrosis factor
Tumour necrosis factor is a trimeric molecule, each subunit of which consists of an antiparallel β sandwich. Individual subunits form the trimer by a novel edge-to-face packing of β sheets. A comparison of the subunit fold with that of other proteins reveals a remarkable similarity to the ‘jelly-roll’ structural motif characteristic of viral coat proteins.
The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games
The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunbiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.
The Safety and Effectiveness of Single and Repeat Dosing of Intra-Articular Anti-Tumour Necrosis Factor Treatment after Failure of Intra-Articular Steroids
Objectives: To determine if intra-articular (ia) anti-tumour necrosis factor (TNF) yielded benefit in patients failing ia steroid injections and determine the safety and durability of single and repeated ia anti-TNF treatment in inflammatory arthritis.
Methods: Patients with inflammatory arthritis having one or two active joints, and having failed previous ia steroids were injected with ia adalimumab or ia etanercept mixed with triamcinolone and lidocaine via a retrospective chart audit.
Results: Twenty-six patients were followed: 18 received ia adalimumab, 12 received ia etanercept and 4 received both. Twenty-five knees, 17 ankles, 1 wrist and 1 PIP were injected of whom 6 had repeated injections to a joint. Nine were on concomitant systemic anti-TNF therapy. Fifteen had RA, 4 had a seronegativearthropathy, 3 had psoriatic arthritis, and 4 had other arthritis. When determining a response to ia anti-TNF for > 2 months in patients with sufficient follow up 13 of 18 receiving iaadalimumab and 6/7 with ia etanercept had benefit. There were no serious adverse events (SAEs) and only one AE in a wrist post ia adalimumab, with rebound inflammation after 6 weeks of marked relief. Two were able to cancel or postpone joint surgery(knee and ankle)and one cancelled an yttrium injection.
Conclusions: There were no SAEs and prolonged benefit was found with ia anti-TNF and steroids and lidocaine compared to previous ia steroids with lidocaine in the majority (20/27). Although not approved for ia administration, ia anti-TNFs may be cost effective in persistent synovitis of one or two joints recalcitrant to ia steroids.
Changes in Lipid Peroxidation, Free Radical Scavengers and Tumour Necrosis Factor-alpha in Serum of Wistar Rats with Induced Thyroid Dysfunction
Aim: To assess the changes in lipid peroxidation, free radical scavengers and tumour necrosis factor-alpha in serum of Wistar rats with induced thyroid dysfunction.
Study Design: An experimental animal study was conducted in which Wistar rats with induced thyroid dysfunction were studied.
Place and Duration of Study: Animal House, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto and Department of Chemical Pathology, Faculty of Medical Laboratory Sciences, Usmanu Danfodiyo University, Sokoto, between June, 2016 and December, 2016.
Methodology: Twenty-one (21) male Wistar rats weighing 140 – 180 grams were randomly divided into three groups. Therefore, each group consists of 7 rats. Euthyroid (control): untreated receiving daily intraperitoneal injection of 0.9% normal saline solution; hypothyroid: treated with daily oral administration of 6-propyl-2-thiouracil (5 mg/100 g) and hyperthyroid: treated with daily intraperitoneal injection of L-thyroxine (0.1 µg/g). At the end of the 30 days treatment, rats were fasted for 12 hours and blood samples were collected under chloroform anaesthesia for the estimation of serum total triidothyronine (tT3), total tetraiodothyronine (tT4), thyroid stimulating hormone (TSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), malondialdehyde (MDA) and tumour necrosis-alpha (TNF-α) using standard techniques. The rats were then scarified by cervical decapitation and slices of liver tissue were made for histological examination.
Results: The result indicated that final body weight, and serum tT3, tT4, SOD, CAT and GPX were significantly (P<0.05; P< 0.001) lower in hypothyroid and hyperthyroid rats while, serum MDA and TNF-α were significantly (P<0.05; P< 0.001) higher in hypothyroid and hyperthyroid compared with euthyroid rats. Serum TSH was significantly (P< 0.001) higher in hypothyroid compared with euthyroid and hyperthyroid rats. Histological examination of the hepatocellular tissue of euthyroid rat revealed normochromic and normocytic cellular architecture. There was polymorphocytic infiltration with mild inflammation and hypochromatic liver in hypothyroid rats while, conspicuous infiltrations of polymorphs in all fields were observed in hyperthyroid rats.
Conclusion: In this study, serum MDA and TNF-α were significantly higher, and SOD, CAT and GPX activities were lower in experimental hypothyroid and hyperthyroid rats. The result therefore suggests that a decreased antioxidant capacity coupled with increased oxidative stress and TNF-α may play an important role in the pathogenesis of hepatic injury due to thyroid dysfunction and underscores the role of antioxidants in reducing oxidative stress associated with thyroid dysfunction.
 Balkwill, F., 2009. Tumour necrosis factor and cancer. Nature reviews cancer, 9(5), pp.361-371.
 Jones, E.Y., Stuart, D.I. and Walker, N.P.C., 1989. Structure of tumour necrosis factor. Nature, 338(6212), pp.225-228.
 Hehlgans, T. and Pfeffer, K., 2005. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology, 115(1), pp.1-20.
 Chia, J. and Pope, J., 2012. The Safety and Effectiveness of Single and Repeat Dosing of Intra-Articular Anti-Tumour Necrosis Factor Treatment after Failure of Intra-Articular Steroids. Journal of Advances in Medicine and Medical Research, pp.39-53.
 Yeldu, M.H. and Ishaq, S., 2017. Changes in lipid peroxidation, free radical scavengers and tumour necrosis factor-alpha in serum of wistar rats with induced thyroid dysfunction. Annual Research & Review in Biology, pp.1-14.