Experimental Study Of Therapy Effect Of Selective COX-2 Inhibitor On Cancer Cachexia

Objective:The experiment objective is to study the effect of celecoxib on cancer cachexia by establishing an experimental cancer cachectic model, observe the influence on animation, metabolism indicators, serum cytokine and further to study the effect of prophylactic use selective COX-2 inhibitor celecoxib on the happen of cancer cachexia as well as to investigate initially the anti-cancer cachexia effect and the possible mechanism.Methods:50 healthy male C57/BL/6 mice, 6-8 weeks,were random divided into 5 groups: healthy control group (HC),cancer cachexia with normal saline group(CC),cancer cachexia with prophylactic group(PG), cancer cachexia with celecoxib group(TG), cancer cachexia withMedroxyprogesterne group(MPA).A suspension of Lewis lung carcinoma cell was inoculated into each mouse to establish cancer cachexia model. The tumor can be touched in each mice injected three to five days later. PG group began to theraping with celecoxib (40mg·kg-1·d-1).On the 19th day, the other mice became thin, skin and fur became coarse, dark and gloomy and less move, the removed tumor weight lessen more than 10% compared to healthy control group , all mice got into cancer cachexia. TG group began to theraping with celecoxib(40mg·kg-1·d-1 )and MPA group began to theraping with Medroxyprogesterone (150mg·kg-1·d-1) and the CC group began to theraping with normal saline for one week. To observe the general condition and cachectic parameter in each group after different drug intervention. The serum levels of biochemical indicator were measured by omni-automatic biochemistry analyzer. The serum levels of cytokine TNF-αand Leptin were measured by RIA. The expression of VEGF in tumor tissue were analyzed by flow cytometry (FLM).The differences in all indicators of each group were observed and contrasted. All data were analyzed with the spss13.0 software and showed by ( x±s), the comparison among multitude simple mean by One-Way analysis of variance (One-Way ANOVA).Results:1 Cancer cachetic mode : A suspension of Lewis lung carcinoma cells were inoculated into each mouse to establish cancer cachectic model. The tumor can be touched in each mice injected three to five days later, there were no obvious changes in spirit and active stage. On the 19th day, the mice became thin, skin and fur became coarse, dark and gloomy, and less move, the removed tumor weight lessen more than 10% compared to healthy control group, drinking and eating reduced obviously, they are weak and prostrate, all mice got into cancer cachexia.2 The Body weight and general condition : At the beginning, the body weight of each group had no notable difference (Ρ>0.05). On the 27th day ,the drinking and eating and general condition of CC group aggravate most obviously. The general condition of TG and MPA was worse than PG. The removed tumor weight of MPA was significant higher than CC(Ρ<0.05),there was no significant difference between CC and other group (Ρ>0.05).The tumor weight of PG was significant lighten than CC(Ρ<0.05).The index of spleen of all tumor beard groups were significant higher than that of HC group(Ρ<0.05), the index of spleen of PG was significant lower than that of CC group(Ρ<0.05).3 Biochemical indicator : All the treated group compared with HC appeared different degree of metabolic exhaustion(Ρ<0.05). The blood glucose of CC was significant lower than any other group (Ρ<0.05),and the cholesterol and the triglyceride were significant higher than that in other groups(Ρ<0.05).The concentration of LDH in tumor tissue homogenate in each group was lower than that in CC(Ρ<0.05). The LDH in PG was significant lower than that in MPA(Ρ<0.05).There was no significant difference between PG and TG(Ρ>0.05).4 Cytokine : The serum levels of TNF-αin HC was obviously lower than that in any other group(Ρ<0.05).The serum levels of TNF-αin each group after treated was significant lower than that in CC(Ρ<0.05). The serum levels of TNF-αin PG and TG was lower than that in MPA(Ρ<0.05),and The serum levels of TNF-αin PG was obvious lower than that in TG. The serum levels of Leptin in CC was significant lower than that in HC, the difference has a statistic significance(Ρ<0.05), and there was no statistic significance between CC and PG,TG,MPA(Ρ>0.05).5 The expression of VEGF in tumor : The expression of VEGF in PG,TG was significant lower than that in CC, the difference has a statistic significance (Ρ<0.05), there was no statistic significance between CC and MPA (Ρ>0.05).The expression of VEGF in PG was lower than that in TG but this difference has no statistic significance(Ρ>0.05).6 The result of correlation analysis : The correlation coefficient between serum Leptin and TNF-αis r =﹣0.778(Ρ>0.05), there was no statistic significance.We cannot think that there has a correlativity between serum Leptin and TNF-α.Conclusions:1 The study has successfully established an experimental animal model that was very similar to human cancer cachexia . It provides great contribution to further study on the happen and prevention and cure of cancer cachexia.2 In cancer cachectic model, there are some frequent indexes disorder such as the removed tumor weight wasting, body fat descending,nutrition exhausting and metabolic disorde,in addition, the serum levels of TNF-αsignificantly raise up and the Leptin descent show that blood glucose as well as fat metabolic disturbance are possibly associated with activity of proinflammatory cytokine in cancer cachexia. The level of serum Leptin may be associated with the descend of body fat .There has no correlativity between serum Leptin and TNF-α.3 Celecoxib can improve the general condition of cancer cacaxia mice, regulate the body metabolic disturbance originated by cancer cachexia, down-regulate the expression of VEGF in tumor tissue and degrade serum level of TNF-α. Accordingly,celecoxib has a significant anti-cancer cachexia effect. Prophylactic use celecoxib can improve the immunity of cancer cachexia mice, show a noticeable anti-cancer cachexia effect .4 MPA can significantly increase the removed tumor weight, degrade serum level of TNF-α, but it has no obvious effect on immunity improvement and down-regulate the expression of VEGF in tumor tissue and inhibit the proliferation of cancer cell.5 These findings suggested that selective COX-2 Inhibitor celecoxib has played a positive role in prevention and cure cancer cachexia. It has provided a expedient experiment evidence for clinical application and may become a new mean of anti-cancer cachexia .