多西紫杉醇同步放射对小鼠Lewis肺癌生长抑制作用及其机理的研究
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摘要
背景:每年全世界大约新增一百万的肺癌患者,其中非小细胞肺癌的发病率约占肺癌发病总数的75%-85%,其2/3的患者确诊时已失去手术机会,即为Ⅲ_B～Ⅳ期患者,预后不良。随机临床试验和meta分析都发现同步放化疗可以有效的提高无法手术切除的Ⅲ期患者的生存率,是目前的标准治疗模式,多西紫杉醇联合同步放射治疗是目前比较推崇的肺癌综合治疗方案。但是,多西紫杉醇同步放射的生物学机制复杂,目前认为可能与细胞周期阻滞、诱导部分细胞凋亡及残留乏氧细胞再氧合有关。涉及基因调控的分子生物学机制尚未明了。
目的:本研究观察多西紫杉醇联合同步放射对小鼠移植性Lewis肺癌的生长抑制作用及对原癌基因表达产物EGFR和凋亡抑制基因bcl-2的影响,初步探讨多西紫杉醇与放射二者之间的可能协同作用机制,希望能够为临床应用多西紫杉醇同步放射提供理论依据。
方法:建立Lewis肺癌移植瘤模型60只,从中选取位于C_(57)BL/6小鼠右后腿的肿瘤直径大小约6mm(5.8mm～6.2mm)的40只,随机分成4组,分别是对照组A(腹腔内注射生理盐水0.2ml,第12,15,19,22,26,29,33,36天各注射1次)、化疗组B(腹腔内注射浓度为200ug/ml的多西紫杉醇1ml,时间同A组),放疗组C(DT=2.5Gy/F,第13,20,27天各照射一次)和同步放化疗组D(化疗同B组,24小时内放疗,放疗同C组)。隔日一次测量瘤块的最长径(a)和与其垂直的短径(b),绘制各组小鼠的肿瘤生长曲线。并记录各组肿瘤直径从6.0mm长至12.0mm的时间,观察肿瘤生长延迟和肿瘤治愈的情况。肿瘤接种第40天处死小鼠,完整剥离瘤体并称重,计算抑瘤率,并用流式细胞术检测各组肿瘤细胞凋亡率及EGFR、Bcl-2蛋白的表达。
结果:同步放化疗组肿瘤体积明显小于其他各组(P＜0.05)。同步放化疗组的绝对延迟时间为(19.8±0.3)d,其标准化的延迟时间为(12.5±0.7)d,增益因子为1.21。与对照组相比,各治疗组的瘤重显著降低(P＜0.01),放疗组、同步放化疗组的瘤重又显著低于化疗组(P＜0.01)。但同步放化疗组与放疗组差异不明显(P＞0.05)。单纯化疗、放疗均可促进肿瘤细胞凋亡(P＜0.01),且单纯放射比多西紫杉醇更能诱导凋亡(P＜0.01),二者联合后能更进一步抑制肿瘤细胞凋亡(P＜0.01)。放疗组和同步放化疗组的Bcl-2表达与对照组相比均有下降(P＜0.05),化疗组对Bcl-2表达无明显影响。而同步放化疗组与放疗组差异不显著(P＞0.05)。5、化疗组、同步放化疗组可以显著抑制肿瘤细胞EGFR的表达(P＜0.01),而放疗组与对照组比较,EGFR表达无明显差异(P＞0.05)。同步放化疗组的EGFR表达分别低于各单独治疗组,差异均具有统计学意义(P＜0.01)。
结论:多西紫杉醇联合同步放射能明显抑制Lewis肺癌移植瘤的生长,其抑制作用可能与二者协同诱导肿瘤细胞凋亡,协同抑制EGFR的表达和放疗抑制Bcl-2蛋白表达有关。
Background:Almost one million new cases of lung cancer occur worldwide each year.Non-small cell lung cancer(NSCLC)accounts for approximately 75%-85%of all cases,2/3 of patients confirmed to have been lost surgery, which isⅢ_B-Ⅳpatients with poor prognosis.Randomized clinical trials and meta-analysis found that concurrent radiochemotherapy can effectively raise the survival rate of the unresectable patients with StageⅢand is the current standard treatment modalities,docetaxel-based concurrent radiochemotherapy is one of the relatively respected comprehensive treatment of lung cancer. However,the biological mechanism of concurrent radiochemotherapy is complex,now it is thought to be related to cell cycle arrest,inducing cell apoptosis and re-oxygenation of the redidued hypoxia cells.The molecular biology mechanisms of gene regulation have not yet clear.
Objective:To investigate the efficacy of docetaxel-based concurrent radiochemotherapy in inhibiting the growth of Lewis lung cancer in vivo, explore the effect of inducing apoptosis,inhibiting bcl-2 and EGFR in the models,study the maybe corrdination mechniam between docetaxel and radiation and provide a theoretical basis for the clinical application of docetaxel-based concurrent radiochemotherapy.
Methods:Treatment was initiated on the 12th day after 60 Lewis lung cancer models established.Every 10 mice bearing 6mm(5.8-6.2mm)xenograft tumor were assigned randomly into cohorts A,B,C and D.Group A(control group)received 0.2ml saline water intraperitoneally on day12,15,19,22,26,29,33,36.Group B received 1ml(200ug/ml)docetaxel intraperitoneally on day12,15,19,22,26,29,33,36.Group C delivered radiation on day13,20,27 to dose 7.5Gy/3F with 6MV X rays.Group D was given induction chemotherapy just same as Group B and concurrent radiation just like Group C within 24 hours after chemotherapy.The tumor volume was measured respectively before the mice were sacrificed on the 40th day and drawed the mice tumor growth curve.Observed the tumor growth delay and calculated the enhancement factors.The characters of apoptosis,expression of bcl-2 and EGFR were detected by Flowcytometry.
Results:The xenograph volume of Group D was significantly smaller than Group A,B and C.For tumor growth delay analysis in the 40 mice,the absolute growth delay(AGD)for Group B and C were(7.3±1.1)and (10.3±1.0)d,respectively.The AGD and the normalized growth delay in Group D were(19.8±0.3)and(12.5±0.7)d,respectively.The enhancement factors was 1.21.The tumor weight of Group B,C,D was significantly lower than Group A(P＜0.01),but there was no significant meaning between the Group C and D(P＞0.05).The apoptotic rate of Group B and C were significantly higher than Group A(P＜0.01),and Group D was significantly higher than Group A, B and C(P＜0.01).The EGFR expression in Group D was significantly lower than Group A,B and C(P＜0.01).And the Bcl-2 expression in Group D was lower than Group A and B(P＜0.05).
Conclusions:Concurrent radiochemotherapy can enhance inhibiting growth of Lewis lung cancer in vivo.The mechanism may be correlated with inducing cell apoptosis,depressing EGFR expression and inhibiting bcl-2 expression by radiotherapy.
目的:本研究观察多西紫杉醇联合同步放射对小鼠移植性Lewis肺癌的生长抑制作用及对原癌基因表达产物EGFR和凋亡抑制基因bcl-2的影响,初步探讨多西紫杉醇与放射二者之间的可能协同作用机制,希望能够为临床应用多西紫杉醇同步放射提供理论依据。
方法:建立Lewis肺癌移植瘤模型60只,从中选取位于C_(57)BL/6小鼠右后腿的肿瘤直径大小约6mm(5.8mm～6.2mm)的40只,随机分成4组,分别是对照组A(腹腔内注射生理盐水0.2ml,第12,15,19,22,26,29,33,36天各注射1次)、化疗组B(腹腔内注射浓度为200ug/ml的多西紫杉醇1ml,时间同A组),放疗组C(DT=2.5Gy/F,第13,20,27天各照射一次)和同步放化疗组D(化疗同B组,24小时内放疗,放疗同C组)。隔日一次测量瘤块的最长径(a)和与其垂直的短径(b),绘制各组小鼠的肿瘤生长曲线。并记录各组肿瘤直径从6.0mm长至12.0mm的时间,观察肿瘤生长延迟和肿瘤治愈的情况。肿瘤接种第40天处死小鼠,完整剥离瘤体并称重,计算抑瘤率,并用流式细胞术检测各组肿瘤细胞凋亡率及EGFR、Bcl-2蛋白的表达。
结果:同步放化疗组肿瘤体积明显小于其他各组(P＜0.05)。同步放化疗组的绝对延迟时间为(19.8±0.3)d,其标准化的延迟时间为(12.5±0.7)d,增益因子为1.21。与对照组相比,各治疗组的瘤重显著降低(P＜0.01),放疗组、同步放化疗组的瘤重又显著低于化疗组(P＜0.01)。但同步放化疗组与放疗组差异不明显(P＞0.05)。单纯化疗、放疗均可促进肿瘤细胞凋亡(P＜0.01),且单纯放射比多西紫杉醇更能诱导凋亡(P＜0.01),二者联合后能更进一步抑制肿瘤细胞凋亡(P＜0.01)。放疗组和同步放化疗组的Bcl-2表达与对照组相比均有下降(P＜0.05),化疗组对Bcl-2表达无明显影响。而同步放化疗组与放疗组差异不显著(P＞0.05)。5、化疗组、同步放化疗组可以显著抑制肿瘤细胞EGFR的表达(P＜0.01),而放疗组与对照组比较,EGFR表达无明显差异(P＞0.05)。同步放化疗组的EGFR表达分别低于各单独治疗组,差异均具有统计学意义(P＜0.01)。
结论:多西紫杉醇联合同步放射能明显抑制Lewis肺癌移植瘤的生长,其抑制作用可能与二者协同诱导肿瘤细胞凋亡,协同抑制EGFR的表达和放疗抑制Bcl-2蛋白表达有关。
Background:Almost one million new cases of lung cancer occur worldwide each year.Non-small cell lung cancer(NSCLC)accounts for approximately 75%-85%of all cases,2/3 of patients confirmed to have been lost surgery, which isⅢ_B-Ⅳpatients with poor prognosis.Randomized clinical trials and meta-analysis found that concurrent radiochemotherapy can effectively raise the survival rate of the unresectable patients with StageⅢand is the current standard treatment modalities,docetaxel-based concurrent radiochemotherapy is one of the relatively respected comprehensive treatment of lung cancer. However,the biological mechanism of concurrent radiochemotherapy is complex,now it is thought to be related to cell cycle arrest,inducing cell apoptosis and re-oxygenation of the redidued hypoxia cells.The molecular biology mechanisms of gene regulation have not yet clear.
Objective:To investigate the efficacy of docetaxel-based concurrent radiochemotherapy in inhibiting the growth of Lewis lung cancer in vivo, explore the effect of inducing apoptosis,inhibiting bcl-2 and EGFR in the models,study the maybe corrdination mechniam between docetaxel and radiation and provide a theoretical basis for the clinical application of docetaxel-based concurrent radiochemotherapy.
Methods:Treatment was initiated on the 12th day after 60 Lewis lung cancer models established.Every 10 mice bearing 6mm(5.8-6.2mm)xenograft tumor were assigned randomly into cohorts A,B,C and D.Group A(control group)received 0.2ml saline water intraperitoneally on day12,15,19,22,26,29,33,36.Group B received 1ml(200ug/ml)docetaxel intraperitoneally on day12,15,19,22,26,29,33,36.Group C delivered radiation on day13,20,27 to dose 7.5Gy/3F with 6MV X rays.Group D was given induction chemotherapy just same as Group B and concurrent radiation just like Group C within 24 hours after chemotherapy.The tumor volume was measured respectively before the mice were sacrificed on the 40th day and drawed the mice tumor growth curve.Observed the tumor growth delay and calculated the enhancement factors.The characters of apoptosis,expression of bcl-2 and EGFR were detected by Flowcytometry.
Results:The xenograph volume of Group D was significantly smaller than Group A,B and C.For tumor growth delay analysis in the 40 mice,the absolute growth delay(AGD)for Group B and C were(7.3±1.1)and (10.3±1.0)d,respectively.The AGD and the normalized growth delay in Group D were(19.8±0.3)and(12.5±0.7)d,respectively.The enhancement factors was 1.21.The tumor weight of Group B,C,D was significantly lower than Group A(P＜0.01),but there was no significant meaning between the Group C and D(P＞0.05).The apoptotic rate of Group B and C were significantly higher than Group A(P＜0.01),and Group D was significantly higher than Group A, B and C(P＜0.01).The EGFR expression in Group D was significantly lower than Group A,B and C(P＜0.01).And the Bcl-2 expression in Group D was lower than Group A and B(P＜0.05).
Conclusions:Concurrent radiochemotherapy can enhance inhibiting growth of Lewis lung cancer in vivo.The mechanism may be correlated with inducing cell apoptosis,depressing EGFR expression and inhibiting bcl-2 expression by radiotherapy.
引文
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