卡培他滨对大鼠免疫功能影响的初步实验观察

Experimental observation of capecitabine immunosuppressive effects in rats

目的观察不同剂量卡培他滨(capecitabine,CAP)对大鼠免疫系统影响,探讨其对免疫细胞的影响及作为免疫抑制剂的潜在可能性。方法成年清洁级雄性BN大鼠18只,分为对照组(CON组)、卡培他滨低剂量组(metronomic chemotherapy,MET组)和高剂量组(most tolerance dose,MTD组),分别经胃灌服生理盐水每次1.2 ml、CAP 45 mg/kg和200 mg/kg,一日2次,连续喂服21 d。给药前、给药后第7天、14天和21天测量大鼠体重并采集静脉血3 ml,采用流式细胞和酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)方法检测外周血总淋巴细胞数、T淋巴细胞数、CD4^+和CD8^+T淋巴细胞数以及IL-2和IFN-γ含量。统计分析3组大鼠体重、总淋巴细胞数、T淋巴细胞数、CD4^+、CD8^+T淋巴细胞数和IL-2、IFN-γ变化趋势及相关性。结果3组大鼠于喂养21 d后均健康存活,体重逐渐增加,MET组和MTD组体重增加程度低于CON组,其中MTD组和CON组于喂养21 d体重变化具有统计学意义〔(214.17±20.6)g比(235±5.48)g,P<0.05)〕。MET组和MTD组总淋巴细胞数、T淋巴细胞数、CD4^+和CD8^+T淋巴细胞数均逐渐减少,给药第21天,MET组、MTD组与CON组淋巴细胞总数、T淋巴细胞数、CD4^+和CD8^+T淋巴细胞数差异具有统计学意义(P<0.05),MTD组与MET组间差异无统计学意义(P>0.05)。MET组和MTD组血清IL-2和IFN-γ含量逐渐下降,给药第7天、第14天及21天时3组间差异有统计学意义(P<0.05)。MET组和MTD组总淋巴细胞数、T淋巴细胞数、CD4^+和CD8^+T淋巴细胞数减少与血清IL-2和IFN-γ下降呈正相关性(P<0.05)。结论卡培他滨可降低大鼠外周血淋巴细胞数并抑制IL-2和IFN-γ的分泌,对淋巴细胞的抑制强度与药物剂量呈正相关,可作为一种具有免疫抑制效应的抗肿瘤药物,对肝癌肝移植患者治疗肿瘤复发具有应用价值。

Objective To investigate the immunosuppressive effect of capecitabine(CAP)at different doses in rats and to explore its potential as an immunosuppressant.Methods Eighteen male BN rats were randomly divided into the control group(CON group),CAP low-dose group(metronomic chemotherapy,MET group),and CAP high-dose group(most tolerance dose,MTD group).Three groups were administered with 1.2ml saline,45 mg/kg and 200 mg/kg CAP by gastric gavage,respectively,the administration was performed twice per day and lasted for 21 days.The rat body weight was measured and 3 ml of venous blood was collected before administration and on the 7th,14th,and 21th day of administration.The total number of lymphocytes,T lymphocytes,CD4^+and CD8^+T lymphocytes in peripheral blood were measured by flow cytometry,and the concentrations of IL-2 and IFN-γwere measured by enzyme linked immunosorbent assay(ELISA).Statistical analysis was performed on the changes of body weight,total lymphocyte count,T lymphocyte count,CD4^+and CD8^+T lymphocyte count,the level of IL-2,IFN-γand their correlations in the three groups.Results All the rats in the three groups survived and gained weight gradually after 21 days of feeding.The weight gain of the MET group and MTD group was lower than that of the CON group,and the weight changes of the MTD group and the CON group were statistically significant at the 21th day〔(214.17±20.6)g vs.(235±5.48)g,P<0.05〕.The total lymphocyte count,T lymphocyte count,CD4^+and CD8^+T lymphocyte count of MET group and MTD group decreased gradually.Compared with the CON group,the total lymphocyte count,T lymphocyte count,CD4^+and CD8^+T lymphocyte count of the MET group and the MTD group were significantly decreased on the 21th days after administration(P<0.05).There was no significant difference between the MET groups and MTD groups(P>0.05).Compared with the CON group,the levels of serum IL-2 and IFN-γin the MET group and MTD group gradually decreased on the 7 th,14 th,and 21 th days after administration(P<0.05).The decrease of the total lymphocyte count,T lymphocyte count,CD4^+and CD8^+T lymphocyte count in MET group and MTD group were positively correlated with the decrease of serum IL-2 and IFN-γconcentrations(P<0.05).Conclusion Capecitabine can reduce the lymphocyte count in peripheral blood and inhibit the secretion of IL-2 and IFN-γin rats,thus exhibiting immunosuppressive effect.The T cell suppressive intensity is positively correlated with the drug dose.Capecitabine has potential application value as an anti-rejection drug after liver transplantation.