Effect of Intensity Modulated Radiotherapy Combined with Hormonal Therapy on Fatigue in Patients with Locally Advanced Prostate Cancer
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摘要:目的
评价调强放疗联合内分泌治疗对局部晚期前列腺癌乏力症状的影响。
方法对符合纳入标准的局部晚期前列腺癌患者采用同期三维适形调强放疗联合内分泌治疗。采用FSI(FatigueSymptom Inventory)量表进行长期问卷随访,调查时间分别为治疗前(A)、治疗结束后(B)、治疗结束3月(C)、12月(D)、24月(E)、36月(F)、48月(G)。随访内容包括疲劳程度、对生活质量影响程度及上周疲劳持续时间3个维度。Logistic多分类回归模型评价危险因素。
结果共97例局部晚期前列腺癌患者纳入研究。中位随访时间43.9月。乏力指数与PSA水平、Gleason评分、ECOG评分及文化程度相关(P<0.05);年龄和临床分期与乏力指数无关(P>0.05);多分类回归分析显示PSA水平和ECOG评分是癌症相关性乏力的独立危险因素。疲劳程度在各个随访时间点未体现出差异(P>0.05),但最严重疲乏程度发生在时间点B和C;时间点C、D、E、F和G的疲乏对生活影响积分均高于基线评价,且差异有统计学意义(P<0.05),尤其是对日常活动影响积分、注意力积分和情绪积分。疲乏持续时间呈现波动状态,时间点D、E、F呈明显上升,差异有统计学意义(P<0.05)。
结论ECOG评分高、Gleason≥8分、PSA>20ng/ml、且文化程度高的局部晚期前列腺癌患者,在接受同期放疗联合内分泌治疗后,要关注乏力对生活质量产生的影响,特别是在对日常活动、注意力和情绪方面。
Abstract:ObjectiveTo evaluate the effect of intensity modulated radiotherapy (IMRT) combined withhormonal therapy on fatigue in patients with locally advanced prostate cancer.
MethodsIMRT combinedwith hormonal therapy were administered to the patients with locally advanced prostate cancer who met theinclusion criteria. Long-term follow-up was performed using the Fatigue Symptom Inventory (FSI) beforetreatment (A), at the end of IMRT (B), and three months (C), 12 months (D), 24 months (E), 36 months(F), and 48 months (G) after IMRT. Three dimensions of fatigue were assessed during follow-up: severity,perceived interference with quality of life, and duration in the past week, meanwhile, we used Cox regressionmodel to evaluate the risk factors.
ResultsTotally, 97 patients were enrolled from February 2007 toNovember 2013. Median follow-up time was 43.9 months. The fatigue index was related to the factors ofPSA, Gleason, ECOG and education(P<0.05), however, not related to the age or TNM staging(P>0.05).PSA and ECOG score were the independent risk factors of cancer-related fatigue. No significant differencewas measured in fatigue among each follow-up time points (P>0.05), but the most severe fatigue occurred attime points B and C. The score for interference with quality of life was significantly higher at each followuptime points after the radiotherapy than the baseline (P<0.05), especially the scores for interference withgeneral level of activity, ability to concentrate and mood. The score for duration of fatigue fluctuated acrossthe time points, with significantly increased scores at time points D, E, and F (P<0.05).
ConclusionForlocally advanced prostate cancer patients with a high ECOG score, a Gleason score >8 points, PSA levels>20 ng/ml and high education, the attention should be paid to the interference of fatigue with quality oflife, especially general level of activity, ability to concentrate and mood, after radiotherapy combined withhormonal therapy.
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Key words:
- Prostate cancer /
- Cancer-related fatigue /
- Radiotherapy /
- Hormonal therapy
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0 引言
淋巴瘤是一类源于淋巴造血系统的恶性肿瘤。2011年我国淋巴瘤男性总发病率为5.98/10万,居于男性恶性肿瘤的前十位[1]。传统的淋巴瘤治疗方案包括放疗、化疗和造血干细胞移植,但由于疾病的异质性很强使临床预后并不理想。大量临床研究表明生物治疗对淋巴瘤有良好的疗效,因此寻找生物治疗的潜在靶点,已经成为目前研究的热点。
Toll样受体4(Toll like receptors 4,TLR4)是一种表达于细胞膜表面的模式识别受体,通过对入侵的病原相关分子模式(pathogen-associated molecularpatterns,PAMP)或损伤相关分子模式(damageassociated molecular patterns,DAMP)如:细菌脂多糖(lipopolysaccharides,LPS)、热休克蛋白(heat shock protein,HSP)、透明质酸、纤维连接蛋白等的识别启动机体固有免疫和获得性免疫[2]。TLR4激活后活化多条信号通路,调控细胞因子、共刺激信号分子表达水平的改变从而影响机体的免疫、增殖、凋亡等生理进程[3]。研究证实TLR4与感染、自身免疫性疾病和实体肿瘤的发生密切相关,这提示TLR4可能成为生物治疗的新靶点[4]。因此,本研究拟通过检测8株淋巴瘤细胞株中TLR4的表达情况,筛选出高表达株进行基因测序以排除MyD88 L265P基因突变。在体外实验中观察激活和抑制TLR4对淋巴瘤细胞的增殖和耐药的影响并初步探讨相关机制。
1 材料与方法
1.1 细胞及试剂
人套细胞淋巴瘤细胞株—Maver、Z138,人Burkitt淋巴瘤细胞株—Raji、CA46,人皮肤T细胞淋巴瘤细胞株—Hut-78,人T淋巴母细胞白血病/淋巴瘤细胞株—Jurkat、Jurkat E6-1、Molt-4,人急性单核细胞白血病细胞—THP-1均购自美国ATCC。RPMI1640、IMDM培养液购自美国Gibco公司,胎牛血清购自美国HyClone公司。RNA提取剂(TRIzol)购自美国Invitrogen公司,反转录试剂盒购自美国Thermo公司,SuperReal荧光定量预混试剂增强版(SYBR Green)购自北京天根生化科技有限公司,UniversalGen DNA Kit通用型柱式基因组提取试剂盒购自北京康为世纪生物科技有限公司。引物合成及测序均由上海英骏生物科技有限公司完成,见表 1。LPS购自美国Sigma公司,TAK-242购自法国InvivoGen公司,CCK-8试剂盒购自日本同仁化学研究所。RIPA裂解液购自北京康为世纪生物科技有限公司,BCA蛋白定量试剂盒、SDS-PAGE凝胶配制试剂盒购自北京普利莱基因技术有限公司,兔抗人GAPDH单克隆抗体、小鼠抗人PCNA单克隆抗体、兔抗人P-gp多克隆抗体购自英国Abcam公司,鼠抗人TLR4单克隆抗体购自美国Santa Cruz公司,二抗购自美国LI-COR公司。
表 1 PCR引物序列Table 1 Sequences of PCR primers1.2 方法
1.2.1 细胞培养
Maver细胞采用含10%胎牛血清(FBS)的IMDM培养液(青霉素100 u/ml和链霉素100 μg/ml),Z138、Raji、Jurkat、Jurkat E6-1、Molt-4和THP-1细胞采用含10% FBS的RPMI 1640培养液(青霉素100u/ml和链霉素100 μg/ml),CA46和Hut-78细胞采用含20% FBS的RPMI1640培养液(青霉素100 u/ml和链霉素100 μg/ml),均培养于37℃、5%CO2饱和湿度孵箱中,每2~3天换液并传代,取对数生长期细胞进行实验。
1.2.2 RT-PCR和qPCR检测TLR4 mRNA表达水平
TRIzol试剂提取8株人淋巴瘤细胞株和人急性单核细胞白血病细胞株阳性对照株THP-1的总RNA,应用NanoDrop ND-2000超微量分光光度计检测总RNA浓度及纯度,调整总RNA浓度为400ng/μl。按照Thermo反转录试剂盒说明书将其反转录为cDNA。采用25 μl RT-PCR反应体系,反应条件为:94℃预变性2 min×1;94℃变性30 s,60℃退火30 s,72℃延伸30 s,共33个循环;72℃终末延伸2 min×1。1.5%琼脂糖凝胶电泳,应用SyngeneMultiGenius凝胶成像系统扫描分析。按照SYBRGreen说明书,配制qPCR反应体系20 μl,反应条件如下:95℃预变性15 min×1;95℃变性10 s,58℃退火20 s,72℃延伸30 s,共40个循环。每株细胞设置3个复孔,实验重复3次。应用IQ5软件分析数据,2-ΔΔCt法计算TLR4 mRNA的相对表达水平。
1.2.3 Western blot法检测TLR4蛋白表达水平
取对数生长期细胞,用RIPA裂解液在冰上匀浆裂解15 min,12 000 g离心10 min,取上清液行BCA法蛋白定量。30 μg蛋白上样,10% SDS-PAGE电泳100V 90 min,采用湿法转膜至硝酸纤维素膜(NC膜)上,条件为250 mA 120 min;5%BSA室温封闭1 h后,分别加入鼠抗人TLR4一抗(1:100,95kDa)和兔抗人GAPDH一抗(1:2 000,36 kDa),4℃孵育过夜;TBST洗膜10 min×3次,再加入二抗(1:10 000),室温孵育1 h,TBST洗膜10 min×3次。应用美国LI-COR公司Odyssey双色红外激光成像系统采集图像,用ImageJ软件分析条带灰度,计算TLR4条带与GAPDH条带灰度值之比,实验重复3次。用THP-1细胞作阳性对照
1.2.4 MyD88基因测序
应用康为世纪公司的UniversalGen NDA Kit通用型柱式基因组提取试剂盒提取TLR4高标达细胞株Raji基因组DNA,用NanoDrop ND-2000超微量分光光度计检测总DNA浓度及纯度。PCR扩增基因组中的MyD88基因,反应条件为:94℃预变性2min×1;94℃变性30 s,59℃退火30 s,72℃延伸30 s,共35个循环;72℃终末延伸2 min×1。PCR产物送上海英骏生物科技有限公司测序。
1.2.5 实验分组
将Raji细胞分为四组,空白对照组(PBS对照)、TAK-242组(TLR4抑制剂)、 LPS组(TLR4激动剂)、LPS+TAK-242组(激动剂+抑制剂)。其中TAK-242工作浓度为5 μmol/L,LPS工作浓度为5 μg/ml。
1.2.6 细胞增殖实验
取对数生长期的Raji细胞接种于96孔板,每孔1×105个细胞,每组设4个平行孔,避光正常无药培养48 h。培养结束前4 h每孔加入10 μl CCK-8。用酶标仪检测OD450值,根据吸光度值分析细胞增殖的能力。
取对数生长期的Raji细胞接种于6孔板,每孔1×106个细胞,每组设3个平行孔。避光正常无药培养48 h后收集4组细胞,PBS洗涤,提取蛋白,Western blot检测各组细胞PCNA的表达水平,实验重复3次。
1.2.7 阿霉素耐药实验
取对数生长期的Raji细胞接种于96孔板,每孔1×105个细胞,每组设4个平行孔,每孔培养液中阿霉素达到半数抑制浓度(IC50=12 μmol/L),避光培养48 h。培养结束前4h每孔加入10 μl CCK-8。用酶标仪检测OD450值,根据吸光度值分析细胞增殖的能力。
取对数生长期的Raji细胞接种于6孔板,每孔1×106个细胞,每组设3个平行孔。在阿霉素IC50浓度下避光培养48 h后收集4组细胞,PBS洗涤,提取蛋白,Western blot检测各组细胞P-gp的表达水平,实验重复3次。
1.3 统计学方法
采用SPSS 20.0统计软件进行统计分析,实验数据用均数±标准差(x±s)表示,组间比较用单因素方差分析,两组均数比较用t检验,率的比较用χ2检验。P<0.05为差异有统计学意义。
2 结果
2.1 RT-PCR和qPCR检测8株淋巴瘤细胞株中TLR4mRNA表达情况
结果显示:TLR4 mRNA在8株淋巴瘤细胞株均有表达。其中以Burkitt淋巴瘤细胞株Raji的表达水平最高,差异具有统计学意义(P<0.05),见图 1。
2.2 Western blot检测8株淋巴瘤细胞株中TLR4蛋白表达情况
TLR4 蛋白在8株淋巴瘤细胞株均有表达。其中以Maver、Z138和Raji的表达水平较高,差异有统计学意义(P<0.05),见图 2。所以本研究选择Raji细胞株进行后续实验。
2.3 MyD88基因测序
Raji细胞测序结果显示:位于染色体3p22.2的38182641位点未发生T→C突变(即MyD88 L265P突变),证实MyD88为野生型,见图 3。
2.4 TLR4对肿瘤细胞增殖的影响
LPS组与空白对照组组相比,细胞生长明显加快,差异具有统计学意义(P=0.016)。而TAK-242、LPS+TAK-242组与空白对照组相比,细胞生长差异无显著统计学意义(P=2.19,P=1.85)。这提示TLR4的激活具有促进Raji细胞增殖的作用。
Western blot结果显示LPS组PCNA的表达水平较其他3组明显增强(P=0.009),见图 4。提示增殖相关蛋白PCNA的表达上调可能导致了肿瘤细胞增殖能力的增强。
2.5 TLR4对阿霉素耐药的影响
在阿霉素半数抑制浓度处理下,PBS组、TAK-242组、LPS组和TAK-242+LPS组细胞死亡率分别为:(49.23±2.03)%、(51.41±1.12)%、(24.65±3.17)%和(41.17±2.69)%,其中LPS组细胞的杀伤率与空白对照组细胞相比明显降低(P=0.002),而TAK-242组、LPS+TAK-242组及空白对照组均接近半数杀伤率。提示激活TLR4能够显著增强Raji细胞对阿霉素的耐药性。
Western blot结果显示LPS组P-gp的表达水平较其他3组明显增强(P=0.001),见图 5。提示耐药相关蛋白P-gp的表达上调可能导致了肿瘤细胞耐药能力的增强。
3 讨论
随着肿瘤生物治疗学的不断进步,以利妥昔单抗和PD-1单抗为代表的一批靶向生物制剂在淋巴瘤治疗方向显示出广阔的应用前景[5]。TLR4为Ⅰ型跨膜糖蛋白,可以调控细胞因子、共刺激信号分子表达及细胞的增殖和凋亡及肿瘤微环境的形成。已有多篇文章报道TLR4在多种实体肿瘤组织如乳腺癌、肺癌、肝癌、胰腺癌等肿瘤中高表达,并参与了肿瘤的发生进展、免疫逃逸和耐药,有望成为肿瘤生物治疗的潜在靶点[6-7]。但TLR4在淋巴瘤中的研究鲜有报道。
本实验通过对淋巴瘤细胞株的筛选发现TLR4分子在于中均有不同程度的表达,提示TLR4分子可能参与了淋巴瘤的发生。MyD88是TLR4信号通路中的一个关键胞内衔接分子,包括2个功能域:N端的死亡域和C端的Toll域,其中Toll域易发生L265P突变[8]。L265P突变可以持续放大激活NF-κB通路促使细胞增殖、细胞周期缩短、阻碍细胞分化成熟,从而发展为肿瘤[9]。研究发现多种淋巴瘤中存在MyD88 L265P突变[10-11]:淋巴浆细胞淋巴瘤和ABC型弥漫大B细胞淋巴瘤中MyD88 L265P突变较常见,而在GCB型弥漫大B细胞淋巴瘤和Burkitt淋巴瘤中则极少出现。由于MyD88 L265P突变会干扰TLR4下游通路从而影响功能研究,所以本实验优先选用Burkitt淋巴瘤细胞株Raji进行测序以进一步确认无MyD88 L265P突变发生。测序结果证实Raji细胞株MyD88基因为野生型。故选用Raji细胞进行后续TLR4功能研究。
既往研究已经证实,TLR4可以促进结肠癌和卵巢癌细胞的生长[12]。LPS是革兰阴性菌细胞壁上的PAMP,可以活化TLR4分子同源二聚体。TAK-242是选择性TLR4胞内结构域信号转导抑制剂[13-15]。本实验发现:LPS激活TLR4后Raji细胞增殖明显增强,而TAK-242阻断后Raji细胞增殖状态与正常状态无明显差别。PCNA是一种分子量为36kDa的真核细胞核蛋白,检测PCNA可以客观地评价肿瘤细胞增殖状态,其表达水平与肿瘤的发展和预后高度相关。本研究Western blot检测发现,激活TLR4可明显上调Raji细胞中PCNA的表达水平,推测细胞增殖活性的增强与PCNA表达量升高相关。
淋巴瘤在临床上具有很强的耐药性,这是临床预后较差的重要原因。文献报道TLR4参与了阿霉素和紫杉醇的耐药[16]。本研究也发现激活TLR4可增强肿瘤细胞阿霉素耐药性。P-糖蛋白(P-glycoprotein,P-gp)是一种多药耐药相关蛋白,在阿霉素及其代谢产物的转运方面发挥重要作用[17]。本研究证实,激活TLR4可明显上调Raji细胞中P-gp的表达水平,提示耐药性的增强可能是通过上调P-gp实现的。因此阻断TLR4对于防治淋巴瘤的进展可能有一定作用,但需进一步研究证实。
综上所述,TLR4淋巴瘤细胞中广泛表达,提示TLR4可能参与了淋巴瘤的发生发展。激活TLR4能够通过上调PCNA和P-gp的表达从而促进淋巴瘤细胞的增殖和耐药。TLR4与肿瘤细胞增殖和耐药紧密相关,提示阻断TLR4可能是治疗淋巴瘤的潜在方法。
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表 1 入组患者的临床资料与疲乏指数的关系
Table 1 Relationship of Clinical data and fatigue index of patients enrolled
表 2 癌性相关性乏力的Logistic多分类回归分析
Table 2 Logistic regression analysis of cancer-related fatigue
表 3 各随访时间点FSI积分
Table 3 FSI scores at each follow-up time point
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