癌因性疲乏病因机制的初步研究
摘要
目的:癌症是目前临床危害人类健康和导致死亡的主要疾病。癌因性疲乏(Cancer-Related Fatigue,CRF)是癌症患者最常见的主观症状之一,可由癌症引起,或是癌症治疗的结果。癌症患者的疲乏发生率为34%-76%,接受化疗的病人有75%-96%会产生疲乏,且持续时间长,极大地影响患者的生活质量,成为治疗和康复的重要影响因素。癌因性疲乏是癌症患者在接受治疗过程中和治疗后经常出现的一类综合征。此类疲乏严重影响了患者的生活质量。因此,探索癌因性疲乏的病理生理机制以制定出行而有效的预防和治疗的策略是非常有必要的。目前,我们对癌因性疲乏的病因了解的还很有限,而且对于肿瘤性疾病疲乏的研究、癌症的多种治疗方式与一些共病态表现(如贫血、恶病质、抑郁、睡眠障碍等)的关系还不明确。但在任何一个个体,癌因性疲乏的病因可能都包含了几种生理和生化系统的失调。目前提出的疲乏病因机制假说包括:5-羟色胺(5-HT)失调,迷走传入神经的激活,肌肉的改变和ATP代谢异常,下丘脑-垂体-肾上腺轴功能异常和24小时节律异常以及促细胞素失调。这些假说很大程度上是基于对行为学疲劳的研究的基础上获得的(尤其是慢性疲劳综合症和运动相关性疲劳)。这些疲劳的机制在很多方面为我们将来研究癌因性疲乏的多病因机制给予了理论上的帮助。但是CRF的具体病因及分子生物学机制还有待我们去进一步探索和发现。
方法:
1癌因性疲乏动物模型的建立:BALB/C裸鼠20只,雌雄兼用,重量26-28g,6周龄,人胃癌BGC-823细胞株,取2.5×106/ml细胞浓度,0.2ml/只裸鼠注射。应用水迷宫实验、旷场实验、鼠尾悬挂实验、力竭游泳实验对原位移植癌裸鼠进行行为学检测。
2 ATP在癌因性疲乏中作用的研究:癌因性疲乏动物模型的建立;把裸鼠随机分为正常对照组(10只)、模型对照组(30只)(其中轻度疲乏组10只、中度疲乏组10只、重度疲乏组10只)、治疗组(90只)(其中轻度疲乏组30只、中度疲乏组30只、重度疲乏组30只)(每组再分3个治疗小组分别是参芪扶正注射液注射组、5-氟尿嘧啶注射组、参芪扶正注射液和5-氟尿嘧啶联合注射组,每组各10只);ATP含量的测定采用高效液相色谱法;腓肠肌超微结构电镜观察。
3肾上腺功能变化在癌因性疲乏中的作用:癌因性疲乏动物模型的建立;把裸鼠随机分为正常对照组(10只)、模型对照组(30只)(其中轻度疲乏组10只、中度疲乏组10只、重度疲乏组10只)、治疗组(90只)(其中轻度疲乏组30只、中度疲乏组30只、重度疲乏组30只)(每组再分3个治疗小组分别是参芪扶正注射液注射组、5-氟尿嘧啶注射组、参芪扶正注射液和5-氟尿嘧啶联合注射组,每组各10只);皮质醇含量的测定采用高效液相色谱法;肾上腺皮质超微结构电镜观察。
4 ATP含量在癌因性疲乏患者中的变化:选取癌症患者(均经病理证实且为行胃癌根治术后3个月存活者)120例(内分参芪扶正注射液注射组、参芪扶正注射液和5-氟尿嘧啶注射组、5-氟尿嘧啶注射组、疲乏对照组);高效液相色谱法测定受试者血浆ATP含量。
5血浆皮质醇含量在癌因性疲乏患者中的变化:选取癌症患者(均经病理证实且为行胃癌根治术后3个月存活者)120例(内分参芪扶正注射液注射组、参芪扶正注射液和5-氟尿嘧啶注射组、5-氟尿嘧啶注射组、疲乏对照组);高效液相色谱法测定受试者血浆皮质醇含量。
结果:
1裸鼠原位移植癌的建立:在进食量、体重上轻度疲乏组高于中度疲乏组,而中度疲乏组高于重度疲乏组,各组间比较的P值均<0.05;在造模结束后,三组不同疲乏程度的裸鼠在出现疲乏后出离水迷宫的时间均延长,并与正常对照组有显著差异(P<0.05);而且,重度疲乏组的出离时间明显长于中度和轻度疲乏组(P<0.05);中度疲乏组的出离时间也长于轻度疲乏组(P<0.05);三组不同疲乏程度的模型组裸鼠在悬尾倒挂后,不动时间均明显长于正常对照组,轻度疲乏组短于中度疲乏组(P<0.05),中度疲乏组短于重度疲乏组(P<0.05),重度疲乏组与正常对照组比较(P<0.01);重度疲乏组的裸鼠从开始游泳至力竭的时间明显低于正常对照组(P<0.01)和轻度及中度疲乏组比较,游泳至力竭的时间也低于以上两组(P<0.05),中度疲乏组裸鼠的力竭时间低于正常对照组和轻度疲乏组裸鼠(P<0.05),轻度疲乏组裸鼠的力竭时间低于正常对照组(P<0.05);重度疲乏组裸鼠在中央格滞留的时间明显长于正常对照组、轻度疲乏组和中轻度疲乏组(P<0.05),中度疲乏组的滞留时间长于轻度疲乏组和正常对照组(P<0.05),轻度疲乏组的滞留时间长于正常对照组(P<0.05);重度疲乏组裸鼠的穿行次数少于另外三组(P<0.05),中度疲乏组的穿行次数少于轻度疲乏组和正常对照组(P<0.05),轻度疲乏组的穿行次数少于正常对照组(P<0.05);在竖起时间上,轻度疲乏组裸鼠的竖起时间与正常对照组间无统计学差异,中度疲乏组的竖起时间短于轻度疲乏组(P<0.05),重度疲乏组的竖起时间明显缩短,与轻度疲乏组和正常对照组比较(P<0.05),有重度疲乏组和中度疲乏组比较(P<0.05)。
2 ATP在裸鼠血浆内含量变化及腓肠肌线粒体变化
2.1各疲乏状态治疗组裸鼠的血浆ATP含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
2.2在轻度、中度和重度疲乏组中,肌原纤维间隙水肿、纤维断裂不连续和肌丝溶解的情况以参芪扶正注射液注射组改变轻,以5-氟尿嘧啶注射组改变重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。线粒体的体积肿胀、肌节旁成对线粒体缺失、嵴排列紊乱和消失、外膜不完整等情况以参芪扶正注射液注射组改变轻,以5-氟尿嘧啶注射组改变重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。
3皮质醇在裸鼠血浆内含量变化及肾上腺皮质变化
3.1各疲乏状态治疗组裸鼠的血浆皮质醇含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
3.2在轻度、中度和重度疲乏组中,线粒体和脂滴的水肿、线粒体嵴断裂不连续和空泡化的情况以参芪扶正注射液注射组改变为轻,以5-氟尿嘧啶注射组改变为重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。
4 ATP含量在癌因性疲乏患者中的变化:各疲乏状态治疗组受试者的血浆
ATP含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
5各疲乏状态治疗组受试者的血浆皮质醇含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
结论:
1受试者血浆内ATP含量测定结果与动物模型实验中测定结果存在一致性,说明ATP含量对于癌因性疲乏的发生、发展均有一定的作用,可认为是癌因性疲乏的病因机制之一。
2受试者血浆内皮质醇含量测定结果与动物模型实验中测定结果存在一致性,说明皮质醇含量对于癌因性疲乏的发生、发展均有一定的作用,也即下丘脑-垂体-肾上腺轴的功能变化是癌因性疲乏的病因机制之一。
Objectives: Cancer is the major diseases to current human healt- h. Cancer-Related Fatigue is one of the most common subjective symp- toms in these patients.CRF’s coming is because of cancer or the Cancer treatment results.CRF’s incidence is of 34%-76% and in the patients who has been chemotherapied is of 75%-96%.Cancer-related fatigue (CRF) is one of the most prevalent symptoms patients with cancer experience, both during and after treatment. CRF is pervasive and affects patients’quality of life considerably. It is important,thereofre, to understand the underlyi- ng pathophysiology of CRF in order to develop useful strategies for prev- ention and treatment. At present, the etiology of CRF is poorlyunderstoo- d and the relative contributions of the neoplastic disease, various forms of cancer therapy, and comorbid conditions (e.g., anemia, cachexia, sleep di- sorders, depression) remain unclear. In any individual,the etiology of CR- F probably involves the dysregulation of several physiological and bioch- emical systems.Mechanisms proposed as underlying CRF include 5-HT neurotransmitter dysregulation, vagal afferent active- tion, alterations in muscle and ATP metabolism,hypothalamic– pitui- tary– adrenal axis dy- sfunction, circa- dian rhythm disruption, and cytokine dysregulation. Cur- rently, these hypotheses are largely ba- sed on evidence from other con- ditions in which fatigue is a charact- eristic, in particular chronic fatigue syndrome and exercise-induced fatigue. The mechanisms that lead to fa- tigue in these conditions provide a theoretical basis for future research in- to the complex etiology of this distressing and debilitating symptom. An understanding of relevant mechanisms may offer potential routes for its prevention and treatment in patients with cancer.
Method:
1 The establishment of animal models for the CRF: BALB/C nude mice 20,human’s gastric cancer cell strain BGC-823.Making water maze ex- periment, The tail hanging experiment, experiment of unable to Swimm- ing and open field test to tests animal models’behavioral.
2 The effect of ATP in CRF:Putting the nude mice into the control group- (10), the model group(30),and the treatment group(90).In the treatment group,there are three group:the mild fatigue group(30),the moderate fatigue group(30)and the severe fatigue group(30).In every treatment gr- oup there are three team:shenqifuzhengye injection group(10), shenqifu zhengye and 5-Fu injection(10),5-Fu injection(10). HPLC is the way to determine the content of serum ATP.Musculus gastrocnemius’ultr- astructure is observed by electron microscope.
3 The role of cortisol levels in CRF: Putting the nude mice into the control group(10), the model group(30),and the treatment group(90).In the treatment group,there are three group:the mild fatigue group(30),the moderate fatigue group(30)and the severe fatigue group(30).In every treatment group there are three team:shenqifuzhengye injection group(10), shenqifu zhengye and 5-Fu injection(10),5-Fu injection(10). HPLC is the way to determine cortisol levels. Adrenal cortex’ultrastructure is observed by electron microscope.
4 The change of ATP in CRF’s patients: 120 patients was selected who had been three months after radical operation for carcinoma of stomach.these patients were divided into four groups: shenqifuzhengye injection group, shenqifu zhengye and 5-Fu injection, 5-Fu injection and fatigue group. HPLC is the way to determine the content of serum ATP.
5 The change of cortisol levels in CRF’s patients: 120 patients was selected who had been three months after radical operation for carcinoma of stomach.these patients were divided into four groups: shenqifuzhengye injection group, shenqifu zhengye and 5-Fu injection, 5-Fu injection and fatigue group. HPLC is the way to determine cortisol levels.
Results:
1 Models of nude mice establishing:The mild fatigue group is higher than the moderate fatigue group in food taking and weight,the moderate fatigue group is higher than the severe fatigue group P<0.05.After making models three degrees fatigue mice compared with the control group. In water maze experiment, the time of leaving water maze in the control group was shortest in the test P<0.05,the severe fatigue group was the longest,the moderate fatigue group was shorter than the severe fatigue group, the mild fatigue group was shorter than the moderate fatigue group P<0.05.In the tail hanging experiment, the time of unable moving in the control group was shortest in the test P<0.05, the severe fatigue group was the longest,the moderate fatigue group was shorter than the severe fatigue group, the mild fatigue group was shorter than the moderate fatigue group P<0.05. In the experiment of unable to Swimming, the time of unable to Swimming in the control group was longest in the test P<0.05or P<0.01, the severe fatigue group was the shortest , the moderate fatigue group was longer than the severe fatigue group, the mild fatigue group was longer than the moderate fatigue group P<0.05.In open field test,the result was the same as the above all three tests.
2 The content changing of serum ATP in nude mice and the change of Musculus gastrocnemius’ultrastructure
2.1 The content changing of serum ATP in nude mice :Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the model group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the model group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the model group P<0.05; the model group was?less than the control group P<0.01.
2.2 The change of Musculus gastrocnemius’ultrastructure: The change of shenqifuzhengye injection group was smaller than shenqifu zhengye and 5-Fu injection; the change of shenqifu zhengye and 5-Fu injection was smaller than the model group; the change of he model group was smaller than 5-Fu injection.
3 The content changing of cortisol levels in nude mice and the change of adrenal cortex’ultrastructure:
3.1 The content changing of cortisol levels in nude mice: Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the model group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the model group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the model group P<0.05; the model group was?less than the control group P<0.01.
3.2 The change of adrenal cortex’ultrastructure: The change of shenqifu -zhengye injection group was smaller than shenqifu zhengye and 5-Fu injection; the change of shenqifu zhengye and 5-Fu injection was smaller than the model group; the change of he model group was smaller than 5-Fu injection.
4 The change of ATP in CRF’s patients: The content of serum ATP in the control group was the biggest,;Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the fatigue group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the fatigue group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the fatigue group P<0.05; the fatigue group was?less than the control group P<0.01.
5 The change of cortisol levels in CRF’s patients: The cortisol levels in the control group was the biggest,;Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the fatigue group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the fatigue group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the fatigue group P<0.05; the fatigue group was?less than the control group P<0.01.
Conclusions:
1 The change of ATP in CRF’s patients was the same as that in nude mice.This indicated the content of serum ATP has effect on the taking place and development of CRF.So the ATP is one of the etiological mechanism of cancer-related fatigue.
2 The change of cortisol levels in CRF’s patients was the same as that in nude mice.This indicated the serum cortisol levels has effect on the taking place and development of CRF.So the cortisol levels is one of the etiolo- gical mechanism of cancer-related fatigue,the HPA is one of the etiolo- gical mechanism of cancer-related fatigue.
方法:
1癌因性疲乏动物模型的建立:BALB/C裸鼠20只,雌雄兼用,重量26-28g,6周龄,人胃癌BGC-823细胞株,取2.5×106/ml细胞浓度,0.2ml/只裸鼠注射。应用水迷宫实验、旷场实验、鼠尾悬挂实验、力竭游泳实验对原位移植癌裸鼠进行行为学检测。
2 ATP在癌因性疲乏中作用的研究:癌因性疲乏动物模型的建立;把裸鼠随机分为正常对照组(10只)、模型对照组(30只)(其中轻度疲乏组10只、中度疲乏组10只、重度疲乏组10只)、治疗组(90只)(其中轻度疲乏组30只、中度疲乏组30只、重度疲乏组30只)(每组再分3个治疗小组分别是参芪扶正注射液注射组、5-氟尿嘧啶注射组、参芪扶正注射液和5-氟尿嘧啶联合注射组,每组各10只);ATP含量的测定采用高效液相色谱法;腓肠肌超微结构电镜观察。
3肾上腺功能变化在癌因性疲乏中的作用:癌因性疲乏动物模型的建立;把裸鼠随机分为正常对照组(10只)、模型对照组(30只)(其中轻度疲乏组10只、中度疲乏组10只、重度疲乏组10只)、治疗组(90只)(其中轻度疲乏组30只、中度疲乏组30只、重度疲乏组30只)(每组再分3个治疗小组分别是参芪扶正注射液注射组、5-氟尿嘧啶注射组、参芪扶正注射液和5-氟尿嘧啶联合注射组,每组各10只);皮质醇含量的测定采用高效液相色谱法;肾上腺皮质超微结构电镜观察。
4 ATP含量在癌因性疲乏患者中的变化:选取癌症患者(均经病理证实且为行胃癌根治术后3个月存活者)120例(内分参芪扶正注射液注射组、参芪扶正注射液和5-氟尿嘧啶注射组、5-氟尿嘧啶注射组、疲乏对照组);高效液相色谱法测定受试者血浆ATP含量。
5血浆皮质醇含量在癌因性疲乏患者中的变化:选取癌症患者(均经病理证实且为行胃癌根治术后3个月存活者)120例(内分参芪扶正注射液注射组、参芪扶正注射液和5-氟尿嘧啶注射组、5-氟尿嘧啶注射组、疲乏对照组);高效液相色谱法测定受试者血浆皮质醇含量。
结果:
1裸鼠原位移植癌的建立:在进食量、体重上轻度疲乏组高于中度疲乏组,而中度疲乏组高于重度疲乏组,各组间比较的P值均<0.05;在造模结束后,三组不同疲乏程度的裸鼠在出现疲乏后出离水迷宫的时间均延长,并与正常对照组有显著差异(P<0.05);而且,重度疲乏组的出离时间明显长于中度和轻度疲乏组(P<0.05);中度疲乏组的出离时间也长于轻度疲乏组(P<0.05);三组不同疲乏程度的模型组裸鼠在悬尾倒挂后,不动时间均明显长于正常对照组,轻度疲乏组短于中度疲乏组(P<0.05),中度疲乏组短于重度疲乏组(P<0.05),重度疲乏组与正常对照组比较(P<0.01);重度疲乏组的裸鼠从开始游泳至力竭的时间明显低于正常对照组(P<0.01)和轻度及中度疲乏组比较,游泳至力竭的时间也低于以上两组(P<0.05),中度疲乏组裸鼠的力竭时间低于正常对照组和轻度疲乏组裸鼠(P<0.05),轻度疲乏组裸鼠的力竭时间低于正常对照组(P<0.05);重度疲乏组裸鼠在中央格滞留的时间明显长于正常对照组、轻度疲乏组和中轻度疲乏组(P<0.05),中度疲乏组的滞留时间长于轻度疲乏组和正常对照组(P<0.05),轻度疲乏组的滞留时间长于正常对照组(P<0.05);重度疲乏组裸鼠的穿行次数少于另外三组(P<0.05),中度疲乏组的穿行次数少于轻度疲乏组和正常对照组(P<0.05),轻度疲乏组的穿行次数少于正常对照组(P<0.05);在竖起时间上,轻度疲乏组裸鼠的竖起时间与正常对照组间无统计学差异,中度疲乏组的竖起时间短于轻度疲乏组(P<0.05),重度疲乏组的竖起时间明显缩短,与轻度疲乏组和正常对照组比较(P<0.05),有重度疲乏组和中度疲乏组比较(P<0.05)。
2 ATP在裸鼠血浆内含量变化及腓肠肌线粒体变化
2.1各疲乏状态治疗组裸鼠的血浆ATP含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
2.2在轻度、中度和重度疲乏组中,肌原纤维间隙水肿、纤维断裂不连续和肌丝溶解的情况以参芪扶正注射液注射组改变轻,以5-氟尿嘧啶注射组改变重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。线粒体的体积肿胀、肌节旁成对线粒体缺失、嵴排列紊乱和消失、外膜不完整等情况以参芪扶正注射液注射组改变轻,以5-氟尿嘧啶注射组改变重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。
3皮质醇在裸鼠血浆内含量变化及肾上腺皮质变化
3.1各疲乏状态治疗组裸鼠的血浆皮质醇含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
3.2在轻度、中度和重度疲乏组中,线粒体和脂滴的水肿、线粒体嵴断裂不连续和空泡化的情况以参芪扶正注射液注射组改变为轻,以5-氟尿嘧啶注射组改变为重,参芪扶正注射液和5-氟尿嘧啶联合注射组的改变轻于模型对照组,模型对照组的改变轻于5-氟尿嘧啶注射组。
4 ATP含量在癌因性疲乏患者中的变化:各疲乏状态治疗组受试者的血浆
ATP含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
5各疲乏状态治疗组受试者的血浆皮质醇含量均低于正常对照组。参芪扶正注射液注射组与正常对照组比较P<0.05或P<0.01,与参芪扶正注射液和5-氟尿嘧啶联合注射组比较P<0.05,与5-氟尿嘧啶注射组比较P<0.01,与模型对照组比较P<0.05;参芪扶正注射液和5-氟尿嘧啶联合注射组与正常对照组比较P<0.01,与5-氟尿嘧啶注射组比较P<0.05,与模型对照组比较P<0.05;5-氟尿嘧啶注射组与正常对照组比较P<0.01,与模型对照组比较P<0.05;模型对照组与正常对照组比较P<0.01。
结论:
1受试者血浆内ATP含量测定结果与动物模型实验中测定结果存在一致性,说明ATP含量对于癌因性疲乏的发生、发展均有一定的作用,可认为是癌因性疲乏的病因机制之一。
2受试者血浆内皮质醇含量测定结果与动物模型实验中测定结果存在一致性,说明皮质醇含量对于癌因性疲乏的发生、发展均有一定的作用,也即下丘脑-垂体-肾上腺轴的功能变化是癌因性疲乏的病因机制之一。
Objectives: Cancer is the major diseases to current human healt- h. Cancer-Related Fatigue is one of the most common subjective symp- toms in these patients.CRF’s coming is because of cancer or the Cancer treatment results.CRF’s incidence is of 34%-76% and in the patients who has been chemotherapied is of 75%-96%.Cancer-related fatigue (CRF) is one of the most prevalent symptoms patients with cancer experience, both during and after treatment. CRF is pervasive and affects patients’quality of life considerably. It is important,thereofre, to understand the underlyi- ng pathophysiology of CRF in order to develop useful strategies for prev- ention and treatment. At present, the etiology of CRF is poorlyunderstoo- d and the relative contributions of the neoplastic disease, various forms of cancer therapy, and comorbid conditions (e.g., anemia, cachexia, sleep di- sorders, depression) remain unclear. In any individual,the etiology of CR- F probably involves the dysregulation of several physiological and bioch- emical systems.Mechanisms proposed as underlying CRF include 5-HT neurotransmitter dysregulation, vagal afferent active- tion, alterations in muscle and ATP metabolism,hypothalamic– pitui- tary– adrenal axis dy- sfunction, circa- dian rhythm disruption, and cytokine dysregulation. Cur- rently, these hypotheses are largely ba- sed on evidence from other con- ditions in which fatigue is a charact- eristic, in particular chronic fatigue syndrome and exercise-induced fatigue. The mechanisms that lead to fa- tigue in these conditions provide a theoretical basis for future research in- to the complex etiology of this distressing and debilitating symptom. An understanding of relevant mechanisms may offer potential routes for its prevention and treatment in patients with cancer.
Method:
1 The establishment of animal models for the CRF: BALB/C nude mice 20,human’s gastric cancer cell strain BGC-823.Making water maze ex- periment, The tail hanging experiment, experiment of unable to Swimm- ing and open field test to tests animal models’behavioral.
2 The effect of ATP in CRF:Putting the nude mice into the control group- (10), the model group(30),and the treatment group(90).In the treatment group,there are three group:the mild fatigue group(30),the moderate fatigue group(30)and the severe fatigue group(30).In every treatment gr- oup there are three team:shenqifuzhengye injection group(10), shenqifu zhengye and 5-Fu injection(10),5-Fu injection(10). HPLC is the way to determine the content of serum ATP.Musculus gastrocnemius’ultr- astructure is observed by electron microscope.
3 The role of cortisol levels in CRF: Putting the nude mice into the control group(10), the model group(30),and the treatment group(90).In the treatment group,there are three group:the mild fatigue group(30),the moderate fatigue group(30)and the severe fatigue group(30).In every treatment group there are three team:shenqifuzhengye injection group(10), shenqifu zhengye and 5-Fu injection(10),5-Fu injection(10). HPLC is the way to determine cortisol levels. Adrenal cortex’ultrastructure is observed by electron microscope.
4 The change of ATP in CRF’s patients: 120 patients was selected who had been three months after radical operation for carcinoma of stomach.these patients were divided into four groups: shenqifuzhengye injection group, shenqifu zhengye and 5-Fu injection, 5-Fu injection and fatigue group. HPLC is the way to determine the content of serum ATP.
5 The change of cortisol levels in CRF’s patients: 120 patients was selected who had been three months after radical operation for carcinoma of stomach.these patients were divided into four groups: shenqifuzhengye injection group, shenqifu zhengye and 5-Fu injection, 5-Fu injection and fatigue group. HPLC is the way to determine cortisol levels.
Results:
1 Models of nude mice establishing:The mild fatigue group is higher than the moderate fatigue group in food taking and weight,the moderate fatigue group is higher than the severe fatigue group P<0.05.After making models three degrees fatigue mice compared with the control group. In water maze experiment, the time of leaving water maze in the control group was shortest in the test P<0.05,the severe fatigue group was the longest,the moderate fatigue group was shorter than the severe fatigue group, the mild fatigue group was shorter than the moderate fatigue group P<0.05.In the tail hanging experiment, the time of unable moving in the control group was shortest in the test P<0.05, the severe fatigue group was the longest,the moderate fatigue group was shorter than the severe fatigue group, the mild fatigue group was shorter than the moderate fatigue group P<0.05. In the experiment of unable to Swimming, the time of unable to Swimming in the control group was longest in the test P<0.05or P<0.01, the severe fatigue group was the shortest , the moderate fatigue group was longer than the severe fatigue group, the mild fatigue group was longer than the moderate fatigue group P<0.05.In open field test,the result was the same as the above all three tests.
2 The content changing of serum ATP in nude mice and the change of Musculus gastrocnemius’ultrastructure
2.1 The content changing of serum ATP in nude mice :Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the model group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the model group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the model group P<0.05; the model group was?less than the control group P<0.01.
2.2 The change of Musculus gastrocnemius’ultrastructure: The change of shenqifuzhengye injection group was smaller than shenqifu zhengye and 5-Fu injection; the change of shenqifu zhengye and 5-Fu injection was smaller than the model group; the change of he model group was smaller than 5-Fu injection.
3 The content changing of cortisol levels in nude mice and the change of adrenal cortex’ultrastructure:
3.1 The content changing of cortisol levels in nude mice: Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the model group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the model group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the model group P<0.05; the model group was?less than the control group P<0.01.
3.2 The change of adrenal cortex’ultrastructure: The change of shenqifu -zhengye injection group was smaller than shenqifu zhengye and 5-Fu injection; the change of shenqifu zhengye and 5-Fu injection was smaller than the model group; the change of he model group was smaller than 5-Fu injection.
4 The change of ATP in CRF’s patients: The content of serum ATP in the control group was the biggest,;Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the fatigue group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the fatigue group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the fatigue group P<0.05; the fatigue group was?less than the control group P<0.01.
5 The change of cortisol levels in CRF’s patients: The cortisol levels in the control group was the biggest,;Shenqifuzhengye injection group was?less than the control group P<0.05or P<0.01 ,was more than shenqifu zhengye and 5-Fu injection P<0.05, was more than 5-Fu injection P<0.01, was more than the fatigue group P<0.05;shenqifu zhengye and 5-Fu injection was more than 5-Fu injection P<0.05, was more than the fatigue group P<0.05, was?less than the control group P<0.01; 5-Fu injection was?less than the control group P<0.01, was?less than the fatigue group P<0.05; the fatigue group was?less than the control group P<0.01.
Conclusions:
1 The change of ATP in CRF’s patients was the same as that in nude mice.This indicated the content of serum ATP has effect on the taking place and development of CRF.So the ATP is one of the etiological mechanism of cancer-related fatigue.
2 The change of cortisol levels in CRF’s patients was the same as that in nude mice.This indicated the serum cortisol levels has effect on the taking place and development of CRF.So the cortisol levels is one of the etiolo- gical mechanism of cancer-related fatigue,the HPA is one of the etiolo- gical mechanism of cancer-related fatigue.
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