【作者】 李素萍；

【导师】 矫玮；

【作者基本信息】 北京体育大学 ， 运动人体科学， 2012， 博士

【摘要】 目的：通过制备4T1小鼠乳腺癌模型,施予不同强度的有氧运动、紫杉醇的单独或联合干预,研究运动及其与紫杉醇联合在乳腺癌治疗期的作用,并探讨其可能的机制,为丰富乳腺癌的治疗手段、扩大运动在乳腺癌防治中的应用范围提供实验依据。方法：雌性BALB/c小鼠104只,按体重随机分为正常对照组(N)和模型组。模型组小鼠接种4T1细胞。建模成功后,按体重、瘤大小分为生理盐水组(C)、紫杉醇组(P)、运动1组(E1)、运动2组(E2)、联合1组(EP1)和联合2组(EP2)。P、EPl和EP2组腹腔注射紫杉醇,剂量20mg/kg/w,其它组注射等体积生理盐水。运动强度采用12和17米/分,每次30分钟,每周5次,共5周结果：1.4T1细胞接种在小鼠右腋皮下5天后,均有荷瘤生长,病理学检查为浸润性乳腺癌,造模成功。荷瘤组织ER、PR、Her-2的表达均为阴性。2.接种瘤细胞后,小鼠体重下降。干预结束后,模型各组小鼠的体重均显著低于N组。运动、紫杉醇及联合干预均未能延缓荷瘤小鼠体重下降的情况,表现为从干预开始,模型各组间小鼠的体重均无显著差异。3. P、EP1、EP2和E2组生存时间均延长。EP2组效果显著优于其它组。4.EP2组瘤重、瘤体积、瘤体比显著低于C组。其它干预均未能明显延缓荷瘤增长。5.模型各组小鼠淋巴结中调节性T细胞富集,显著高于N组。EP2组荷瘤、淋巴结中调节性T细胞富集现象明显改善。6.EP2组荷瘤组织TGF-β1与IL-10表达显著下调。7.EP2组S期比例显著降低、早、晚期凋亡比例显著增加。8.EP2组NF-κ Bp65的表达显著下调。EP1、EP2与E2组P-IκBα蛋白的表达显著下调,且EP1、EP2的效果优于P,E2效果优于E1。结论：1.17米/分的中强度运动组小鼠生存时间延长,适度运动有助于荷瘤小鼠带瘤生存。2.17米/分的中强度运动联合紫杉醇有效抑制了乳腺癌模型小鼠荷瘤的生长,运动、紫杉醇的单独干预效果不佳,17米/分的中强度运动可增强紫杉醇的治疗效果。3.通过下调NF-κ Bp65、P-IκBα的表达,减少瘤细胞增殖,改善调节性T细胞在局部富集,削弱瘤细胞的免疫逃逸,促进其凋亡,可能是运动联合紫杉醇影响乳腺癌模型小鼠荷瘤生长的机制之一。更多还原

【Abstract】 PurposeThe aim of this research is to study the effect of aerobic exercise of different intensity, paclitaxel and the combination of them in the treatment period of breast cancer, to explore its possible mechanism by establishing4T1mouse breast cancer model, in order to provide experimental basis for enriching the treatment means of breast cancer and expanding the application range of exercise in the prevention and treatment of breast cnncer.MethodsSix to eight-week-old female BALB/c mice were randomly assigned into two groups of normal control (N,8animals) and model (96animals).For the transplantable tumor model studies, viable4T1breast cancer cells were injected s. c. into the right axilla of BALB/c mice.5days after inoculation, the mice were randomized into six groups:①saline-only (C),②paclitaxel-only(P),③exercise-only in low-intensity (E1),④exercise-only in moderate-intensity(E2),⑤exercise in low-intensity and paclitaxel (EP1),⑥exercise in moderate-intensity and paclitaxel (EP2), with16animals per group. The mice of P, EP1and EP2group received i.p. injections of paclitaxel (20mg/kg/w) during the whole experimental period. The mice of other groups received same volume of saline. Exercise groups performed progressive treadmill running up to12m/min or17m/min at0%grade for30minutes,5d/wk for5weeks.Results1. viable4T1breast cancer cells were injected s. c. into the right axilla of BALB/c mice.5days after inoculation, all mice bore tumor. Model was successfully established. The pathological examination revealed that there was invasive breast cancer. All receptors of estrogen, progestoner, human epidermal growth factor receptor--2are negative.2. After inoculation, the weight of mice loss. The weight of mice in each group of model were significantly lower than weight of mice in N group. There were no significant difference in weight between model mice.3. The survival time of mice was prolonged in the group of P、EP1、 EP and E2, The time was significantly longer in EP2than other groups.4. The weight of tumor^tumor volume and ratio of tumor weight and weight of mice were significantly lower in EP2group than C group. There were no significantly difference between other groups and C group.5. The percentage of regulatory T cell in lymphnode of mice was significantly higher in model groups than N group. The percentage of regulatory T cell in tumor and lymphnode of mice were significantly lower in EP2group than C and P group.6. The expression of transforming growth factor-β1and interleukin10of mice were significantly lower in EP2.7. The percentages of S phase was significantly lower and rate of early and late apoptosis cells of mice were significantly higher in EP2.8. The expression of nuclear factor-kappaB p65. phospho-inhibitory subunit of κB-α of mice were lower in EP2. The expression of p-IκBα of mice was also lower in EP1and E2group, and the effect on p-IκB was better in EP1and EP2than P group, moreover, the effect on p-IκB was better in E2than E1group.Conclusion1. The survival time of mice was longer in E2,17m/min moderate intensity exercise can prolong the survival time with tumors in vivo for mice. 2.17m/min moderate intensity exercise combined with paclitaxel can effectively inhibit the growth of tumor, the intervention effect of exercise、paclitaxel alone is ineffective.17m/min moderate intensity Exercise may enhance the anti-cancer effect of paclitaxel.3. One of mechanisms of exercise combined with paclitaxel may have a role in tumor growth is that exercise may down-regulated the expression of NF-κ Bp65and P-IκBα, reduce proliferation of tumor cells, reduce the percentage of regulatory T cell in tumor and lymphnode of mice, weaken the immune escape of tumor cells, induce apoptosis of tumor cells.更多还原