【作者】 王瑜歆； 徐峰； 吴英良； 曾昭蕾； 吴明玮； 冼励坚； 刘广宣； 臧凌鹤； 李经才；

【Author】 Wang Yuxin~1,Xu Feng~1,Wu Yingliang~1,Zheng Shaolei~2,Wu Ming-Wei~2,Xian Li-Jian~2 Liu Guangxuan~3,Zhang Linghe~1,Li Jingcai~1(1 Chronobiological Lab Shenyang Pharmaceutical University Shenyang 110016 China, 2.Cancer Center;Sun Yat sen University;Guangzhou;Guangdong;510060;P.R.China;3 Liaoning tumor hospital 110042 China.)

【机构】 沈阳药科大学； 中山大学肿瘤防治中心； 辽宁省肿瘤医院；

【摘要】 目的:探索顺铂、阿霉素、环磷酰胺（CAP）不同时间联合化疗对血象的影响,找出比联合化疗血液毒性最大和最小的给药时间。方法:肉瘤S₁₈₀荷瘤小鼠,按昼夜六个不同时间点（10:00、14:00、18:00、22:00、02:00、06:00 h）给予CAP联合化疗,考察白细胞总数、淋巴细胞,中性粒细胞、红细胞、血小板计数、血红蛋白、粒细胞集落刺激因子、骨髓细胞周期分布和骨髓细胞凋亡相关蛋白caspase-3表达的变化。结果:CAP联合化疗在开灯前2小时到开灯后2小时应用对外周血WBC计数的抑制作用最强,达到76%以上;在关灯前2小时到关灯后2小时对WBC计数的抑制作用最弱;CAP联合化疗在关灯后2小时对淋巴细胞的抑制作用最弱,而其余时间联合化疗对淋巴细胞的抑制作用均很强,抑制率都达到80-90%;CAP联合化疗在开灯后6小时对中性粒细胞计数的抑制作用最强,在开灯前2小时到开灯后2小时对外周血中性粒细胞计数的抑制作用最弱,CAP联合化疗对淋巴细胞的影响大于对中性粒细胞的影响。CAP联合化疗在关灯后6小时对G-CSF的抑制作用最强,其余时间CAP联合化疗对G-CSF水平没有显著影响;CAP联合化疗对红细胞数和血红蛋白没有显著影响。CAP联合化疗在开灯前2小时对血小板的抑制达51.3%,其余时间对血小板没有显著影响。CAP联合化疗使荷瘤小鼠骨髓细胞G₁期比例减少、SubG₁期增多,在开灯前2小时及整个光照期此影响最强,在关灯前2小时到关灯后2小时,这种影响较弱。CAP联合化疗在光照期使caspase-3活化,而关灯后caspase-3活化减少。结论:CAP联合化疗在光照期使caspase-3活化,活化片段促进骨髓细胞凋亡,使骨髓细胞处于SubG₁期增多,从而抑制白细胞的释放,特别对中性粒细胞和淋巴细胞的抑制作用最强。因此,CAP联合化疗在暗时相末期和光照期血液毒性最大,在关灯前2小时开始血液毒性减弱。更多还原

【Abstract】 Objective:Search the time-dependent effect ofCyclophosphamide-Cisplatin-Adriamycin combined chemotherapy on blood cells and bone marrow in tumor transplanted mice。Methods:S₁₈₀tumor transplanted mice were firstly divided into six groups,and then each group was further divided into 2 groups,one was injected（ip.）with CTX(20 mg·kg^-1),DDP(1 mg·kg^-1),at different time（10:00 h,14:00h,18:00h,22:00h,02:00 hand 06:00 h）,respectively each day,anothergroup as the control. ADM(1 mg·kg^-1)was administrated every three days In all CAP groups.Seramwas collected for the determination of circadian rhythmof blood WBC,lymphocyte,neutrophil,RBC,hemoglobin,blood platelets, granulocyte colony stimulating factor（G-CSF）at the time of CAP treatment on the tenth day after drug administrtion,,and then the distribution of bone marrow cell cycle and expression of apoptosis-related protein caspase-3 were determined.Results:The peripheral white blood cells was inhibited greatly by CAP combined chemotherapy from 10 to 14HALO（hours after light onset）,the inhibition ratio came to 76%.The weakest inhibition time of lymphocyte was 14 to 18HALO and the inhibition ratio were 80-90% at the other times.The depressant effect on neutrophil was weaker from 10 to 14HALO.The strongest inhibition time on G-CSF was at 10HALO.And there was no significant effect on G-CSF at other times. CAP combined chemotherapy has no significant effect on RBC and hemoglobin,and the inhibition ratio to PLTwas 51.3%at 10HALO.In the cell cycle of bone marrow,the proportion of G1 phase degrade and SubG1 phase increased after CAP combined chemotherapy,these effects were strongest at light time and weak from 14 to 18HALO.The tumor cell apoptosis-related protein caspase-3 was activated at light time and opposite at the dark time.Conclusion:the CAP combined chemotherapy could activate caspase-3, promote myeloid cell apoptosis.More cells rest on SubG1 phase,therefore inhibit the white blood cell formation,especially inhibit neutrophiland lymphocyte.the greatest hematotoxicity at the end of dark phase and light time.Hematotoxicity weaken from 10HALO.更多还原