Association of IL-1beta gene polymorphism with cachexia from locally advanced gastric cancer

BACKGROUND: IL-1beta has been implicated in inflammatory episode. In view of the inflammatory nature of cancer cachexia, we determined the predictive value of IL-1B-31 T/C, -511 C/T, +3954 C/T and IL-1RN VNTR gene polymorphisms on the occurrence of cachexia associated with locally advanced gastric cancer. METHODS: The study included 214 patients and 230 healthy volunteers. Genomic DNA was prepared from peripheral blood leukocytes. Genotypes and allele frequencies were determined in patients and healthy controls using restriction fragment length polymorphism analysis of polymerase chain reaction products. RESULTS: The overall frequencies of IL-1B-31 T, -511 T, +3954 T and IL-1RN VNTR alleles in patients with locally advanced gastric cancer were all comparable with those in controls. No significant differences were found in the distribution of IL-1B-31 T, -511 T and IL-1RN VNTR between patients with cachexia and without. Patients with cachexia showed a significantly higher prevalence of IL-1B+3954 T allele than those without (P = 0.018). In a logistic regression analysis adjusted for actual weight, carcinoma location and stage, the IL-1B+3954 CT genotype was associated with an odds ratio of 2.512 (95% CI, 1.180 – 5.347) for cachexia. CONCLUSION: The IL-1B+3954 T allele is a major risk for cachexia from locally gastric cancer. Genetic factors studied are not likely to play an important role in the determination of susceptibility to locally advanced gastric cancer

Metabolic and morphological alterations induced by proteolysis-inducing factor from Walker tumour-bearing rats in C2C12 myotubes

BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model. © 2008 Yano et al; licensee BioMed Central Ltd

Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia

Abstract: Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-alpha were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib

The effect of endurance-type exercise training on growth mediators and inflammatory cytokines in pre-pubertal and early pubertal males.

Recent studies demonstrate an unexpected reduction in circulating levels of IGF-I after 5 wk of endurance-type exercise training in adolescent boys and girls and prepubertal girls. We hypothesized that the reduction in IGF-I would be accompanied by a training-associated stimulation of proinflammatory cytokines IL-1beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), each of which can inhibit the GH-->IGF-I axis. Healthy boys (age range 9-11 y old, mean Tanner 1.7) volunteered for the study and were randomized to control (n = 14) and training groups (n = 12) for 5 wk. After the intervention, significant increase in fitness was observed in the training group but not control group. Although IGF-I was correlated at baseline to peak oxygen consumption in all subjects, there was a significant decrease in IGF-I and IGF binding protein-3 in the training subjects (-12.8 +/- 7.3% and -17.5 +/- 7%, respectively, p < 0.05). In contrast, IGF binding protein-2, known to inhibit anabolic effects of IGF-I, increased in the training subjects (27.8 +/- 11%, p < 0.02) as did IL-1beta and TNF-alpha (51.5 +/- 30.22%, p < 0.02, and 44.5 +/- 23.2%, p < 0.02, respectively). Finally, we also found that GHBP was inversely correlated with fitness, suggesting altered GH function in more-sedentary boys. Thus, these data support the hypothesis that a sustained increase in physical activity can stimulate proinflammatory cytokines, which may contribute to suppression of the GH-->IGF-I axis. Physical activity can influence growth and development through its influence on anabolic and catabolic mediators