The Occurrence And Therapy Of Experimental Cancer Cachexia

Objective: Established an experimental cancer cachectic model and therapies with different dose Indomethacin (IN), to observe physiological conditions, biochemical indicators, serum Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α), the expression of bcl-2 gene, the proliferation and apoptosis of cancer cell. The study is to reveal the relationship between cytokines and experimental cancer cachexia as well as the effect of IN on the cachectic mice.Methods: 64 healthy male BALB/c mice were randomized into 5 groups: healthy control group (HC), cancer cachexia with normal saline group (CC), cancer cachexia with IN 0.5(mgï¹’kg^-1ï¹’d^-1) group (IN1), cancer cachexia with IN1.0 (mgï¹’kg^-1ï¹’d^-1) group (IN2) and cancer cachexia with IN2.0 ( mgï¹’kg^-1ï¹’d^-1) group (IN3). In"CC","IN1","IN2"and"IN3"group, a suspension of 106 murine colonic adenocarcinoma cells (colon26) was inoculated into each mouse to establish cancer cachectic model. A week later, some mice became listless and less move, much thinner than before. To observe these cachectic parameter and some indicators of proliferation and apoptosis etc in each group after injected different dose IN into mouse's abdominal cavity. The serum levels of biochemical indicator were measured by the omni-automatic biochemistry analyzer. The serum levels of cytokine IL-6 and TNF-αwere measured by the ELISA (enzyme-linked immunosorbent assay) way. The expression of bcl-2 and the distribution of cancer cell cycle in tumor tissue were also analyzed by the flow cytometry(FLM).At the 16th day, 38 mice were killed. The rest mice were injected with the same dose IN and normal saline to observe the life span of mice. The differences in all indicators of each group were compared and contrasted. All data were showed by ( x±s) and analyzed with the spss12.0 software, including T-test, Q-test, One-Way analysis of variance (One-Way ANOVA).Results: 1 Cancer cachexia model: 3⁵ days later, in"CC","IN1","IN2"and"IN3"group, tumor was touched; mice become listless and less move. There were no obvious changes in eating and drinking. 7⁸ days later, tumor body grew about 1cm3 or so. Mice became thin, skin and fur became coarse, dark and gloomy. Their activities were slower than before and the spirit became worse. Drinking and eating reduced obviously. All mice got into cancer cachexia 9 days later. After therapies with IN for a week, some physiological conditions had been improved. 2 Body weight: At the beginning, body weight of all group had no notable difference (Ρ>0.05). The mice were executed at the 9th day. The non-tumor body weight in"CC","IN1","IN2","IN3"group was significantly higher than that in"HC"group (Ρ<0.05). There was significant difference in the non-tumor body weight between"IN","IN2","IN3"group and that in"CC"group (Ρ<0.05). There was no significantly difference in the tumor body weight among the last four groups (Ρ>0.05). 3 Biochemical indicator: There was no significant difference in the level of serum total protein among all groups (Ρ>0.05). The level of serum albumin, glucose in"CC"group was significantly lower than that in"HC"group (Ρ<0.05). The level of serum LDH in"CC"group was significantly higher than that in"HC"group (Ρ<0.05). The level of serum albumin, glucose in"IN1","IN2"group was significantly higher than that in"CC"group (Ρ<0.05). The level of serum LDH in"IN1","IN2"group was significantly lower than that in"CC"group (Ρ<0.05). The level of serum glucose in"IN3"group was significantly higher than that in"CC"group (Ρ<0.05). But there was no significantly difference in the serum albumin, LDH between"IN3"group and"CC"group (Ρ>0.05). 4 Cytokine: The serum levels of IL-6 and TNF-αwere no measured in"HC"group. Compared with"HC"group, the serum levels of IL-6 and TNF-αwere very high in"CC"group. The serum levels of IL-6 and TNF-αin"IN1","IN2"group were significantly down-regulated than that in"CC"group (Ρ<0.05). But there was no significantly difference in the serum levels of IL-6 and TNF-αbetween"IN3"group and"CC"group (Ρ>0.05). 5 bcl-2, the proliferation and apoptosis of cancer cell: After therapies with IN, the expression of bcl-2 in"IN1","IN2"group was down-regulated, the apoptosis rate of cancer cell was higher than that in"CC"group (Ρ<0.05). There was no significant difference in the expression of bcl-2 and the apoptosis rate of cancer cell between"IN3"group and"CC"group (Ρ>0.05). Compared with"CC"group, in"IN1","IN2"group the ratio of cancer cells in"G0/G1"stage was increased, but decreased in the"S"stage (Ρ<0.05). So the percent of the proliferation index (PI) in"IN1","IN2"group was significant lower than that in"CC"group. There was no significant difference in the ratio of each stage and PI percent between"IN3"group and"CC"group (Ρ>0.05). 6 Life span: The average life span of mice in"CC"group was 35.3 days. After therapy, the life span of mice in"IN1","IN2"group became longer than that in"CC"group (Ρ<0.05). There was no significant difference in the life span between"IN3"group and"CC"group (Ρ>0.05).Conclusions:1 The study had established an experimental cancer cachexia model successfully that was very similar human's. It provides great contribution for further studying cancer cachexia.2 In cancer cachexia model, there are some frequent indexes such as body weight wasting, nutrition exhausting, metabolic disorder and so on. The high levels of serum cytokines IL-6, TNF-α, IL-1 etc are possibly associated with cancer cachexia. It is probably one of the most important mechanisms that lead to cancer cachexia.3 Middle and low dose IN is able to improve general symptom, increase non-rumor body weight, regulate substance metabolism, down-regulate the levels of cytokines etc in cancer cachexia model.4 High doses IN may only to improve the condition of cancer cachexia. It can't regulate obviously the biochemical indicators and the levels of serum cytokine.5 IN can improve cancer cachexia by two kinds of ways. First way is the mechanism depending on cycloxygenase cyclo-oxygenase (COX). NSAIDs may improve the systemic inflammatory reaction and inhibit inflammatory cytokines through inhibiting the product COX2 that comes from arachidomic acid metabolism. Secondly, IN can induce cancer cell to apoptosis and necrosis through down-regulating the expression of bcl-2 mRNA, IN can also inhibit the proliferation of cancer cell through regulating the expression of cyclic protein and the secondary distribution of cell cycle.