AntiTNFa Treatment of Cancer Cachexia

Several studies have demonstrated the role of anti-TNF-a treatment in animal models of cachexia. Sherry et al. studied the effect of anti-TNF-a immunoglobulin treatment in C57B1/6 mice bearing a methylcholanthrene-induced sarcoma that produced TNF-a. The anti-TNF-a treatment resulted in a significant reduction of weight loss, protein loss and fat loss. It was concluded that neutralising endogenous TNF-a production with antibodies offers the potential to reduce tissue wasting associated with neoplastic disease [36].

An animal study testing the ability of TNF-a antibody blockade to ameliorate cachexia in nude mice bearing xenografted human melanoma A375S2 tumours was performed by Centocor Inc. [37]. The murine antibody A2 (mA2), an antihuman TNF-a antibody (murine version of inflix-imab) and chimeric V1q (cV1q), an anti-mouse TNF-a antibody, were used to treat tumour-bearing animals. The combination of anti-human TNF-a (mA2) and anti-mouse TNF-a (cV1q) significantly inhibited weight loss in human melanoma tumour-bearing animals compared to control antibody-treated animals. These findings indicate that TNF-a participates in weight loss in human melanoma tumour-bearing animals and that antibody blockade of TNF-a activity attenuates tumour-induced cachexia in this model.

Siegel et al. (1995) evaluated the ability of the anti-TNF-a monoclonal antibody infliximab to neutralise the in vitro and in vivo biological effects of TNF-a. It was found that repeated administration of infliximab to transgenic mice that constitutively express human TNF-a achieved significant weight gain and prevented subsequent mortality compared with the control group [38].

Torelli et al. (1999) examined food intake and body weight among tumour-bearing rodents treated with a dimeric, pegylated 55-kDa TNF-a inhibitor. Tumour-bearing rodents received either active agent or vehicle alone. Mice that received the TNF-a inhibitor consumed more calories ad libitum over a 1-week period than those receiving only vehicle. The mice that received the TNF-a inhibitor had an increase in body weight [39].

Anti-TNF-a treatment has shown therapeutic effect in the treatment of cachexia associated with Trypanosoma cruzi infection [40], AIDS and/or tuberculosis [2,41].

A pilot study of anti-TNF-a therapy in patients with myelofibrosis with myeloid metaplasia reported that etanercept, a soluble TNF-a receptor fusion protein that blocks TNF activity, can palliate constitutional symptoms such as drenching night sweats, profound fatigue, and unintentional weight loss. Improvements were seen in seven of seven patients with unintentional weight loss, and 10 of 20 patients with fatigue [42].

A prospective clinical study in rheumatoid arthritis (RA) showed evidence that anti-TNF-a therapy was associated with weight gain in 40 of 46 patients (87.5%). Thirty of these patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6, and then every 8 weeks, and 16 patients received subcutaneous etanercept 25 mg twice weekly. Mean follow-up time was 10.7 months. The mean initial weight was 70.1 kg and the mean final weight was 73.3 kg, corresponding to a mean weight gain of 3.2 kg [43].



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