模拟调强放疗模式对人鼻咽低分化鳞癌细胞株生物效应影响研究
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摘要
目的:
鼻咽癌是人类常见的恶性肿瘤之一,尤其在我国南方高发,放射治疗作为首选治疗。调强放射治疗(intensity-modulated radiation therapy IMRT)技术作为先进放疗技术的代表,突破了传统常规放疗的规则大野照射,以不规则的多个子野从多个角度在保护危及器官及正常组织的同时,最大限度的给予肿瘤区域以较高剂量照射;IMRT还可实现同时补量技术,在治疗次数相同的情况下,给不同的靶区不同剂量。以期提高局控率并减少周围正常组织损伤,因而成为临床肿瘤放射治疗走向精确定位、精确计划设计、精确治疗的标志。近年来,IMRT因其技术优势广泛应用于临床肿瘤放射治疗实践中,如头颈部肿瘤、前列腺癌、乳腺癌、肺癌等。IMRT在物理学上的优势是显而易见的。关于IMRT放疗近期疗效的报道很多,而且大多数结果尚属满意,但至今没有大范围的、有说服力的这种治疗改善了预后的资料。因此推测这一技术在在生物学上可能存在不足之处。因为治疗技术的复杂性,使在常规照射时一次性给予的剂量分成了多次给予,尤其是MLC静态IMRT技术大大延长了照射时间。常规2Gy的照射1～2min即可完成,而IMRT则常常需要20～40min。这样单位时间内肿瘤吸收剂量就大大降低,有人将这种情况称为“相对剂量率降低”。这种照射模式所致“相对剂量率降低是否影响肿瘤细胞的杀灭”已成为临床放射生物学的热点问题。多年来,人们应用细胞培养、免疫组化、分子生物学技术等对肿瘤细胞相关基因蛋白表达情况进行了研究,积累了大量资料。也有作者就离体细胞IMRT照射后,细胞存活曲线的变化进行过研究,从而推断IMRT照射时间延长,可能导致亚致死性损伤修复增加,放射生物效应降低,但其确切影响仍不清楚,未见其他方面深入的报道。放射治疗模式的改变是否会影响肿瘤细胞的生物效应尚未明确,是否要对IMRT照射模式进行剂量补偿亦尚未定论。文献报道,影响细胞放射敏感性的生物因素主要包括DNA损伤的修复、细胞周期、及细胞凋亡。因此本研究旨在通过给予人鼻咽低分化鳞癌细胞株(CNE-2)不同模式照射,探索IMRT治疗模式对CNE-2生物效应的影响。为今后IMRT在临床上的广泛应用,放疗剂量的调整,缩短照射时间,从而提高肿瘤局控率,进一步提高远期生存率,提供实验依据。并依据检测指标的变化,为患者制定个体化的放疗方案,如:确定分割剂量,选择照射时间,提供理论依据。
方法:
选取CNE-2为实验对象,分为空白对照、常规照射、模拟IMRT(按设计要求对各个照射剂量点进行照射,每个剂量点分5次照射,其间分别间隔8.0-8.5min, 35min完成)3组,分别给予6MV-X 2、4、6、8Gy4个剂量点的照射;1)运用克隆形成实验(courtenay assay),检测不同照射模式下CNE-2的存活分数; 2)运用四氮唑蓝法(MTT)进一步验证克隆形成实验的结果;3)运用流式细胞仪(FCM)检测不同照射模式下CNE-2的细胞周期分布及凋亡比例;4)应用RT-PCR及Western blotting方法,检测CNE-2在不同照射模式下,与DNA损伤修复相关的Ku、ATM转录水平及蛋白表达;检测与细胞周期调控相关的Cyclin B1、Cyclin D1的转录水平及蛋白表达,检测与细胞凋亡调节相关的Bcl2、Bax的转录水平及蛋白表达。
结果:
1.克隆形成检测细胞存活分数:
1)CNE-2α/β值为13.177Gy,在2、4、6、8Gy剂量点,常规照射组:SF值分别为0.225,3±0.017,7、0.013±0.002,0、0.002,6±0.000,6和0.0,002±0.000,1,模拟IMRT组:SF分别为0.335,3±0.016,7、0.060,7±0.009,3、0.006,9±0.000,9和0.000,6±0.0,003;模拟IMRT组的SF均高于常规照射组。
2)根据线性二次方程拟合的CNE-2细胞存活曲线,常规放疗组:α、β、N、D0、Dq值分别为0.674,8、0.051,2、1.890,0、0.885,0、0.563,0,模拟IMRT组:α、β、N、D0、Dq值分别为0.537,7、0.026,8、2.610,0、0.986,0和0.946,0;α_(常规)>α_(IMRT),β_(常规)>β_(IMRT),N_(常规)〈N_(IMRT),D_(0常规) 2.MTT检测细胞增殖比例:
CNE-2在2、4、6、8Gy剂量点,常规照射组:细胞增殖比例分别为0.598,7±0.021,7、0.455,7±0.053,7、0.235,3±0.045,3、0.056,7±0.018,3;模拟IMRT组:细胞增殖比例分别为0.682±0.055,0、0.528,3±0.074,3、0.322,3±0.002,0、0.091,7±0.022,3;模拟IMRT组的增殖比例均高于常规照射组。
3.流式细胞术检测细胞周期分布(%):CNE-2在2、4、6、8Gy剂量点
1)常规照射组:G2期细胞比例分别为26.77±0.43、38.33±1.77、46.57±1.43、66.97±1.47;模拟IMRT组:G2期细胞比例分别为21.07±0.87、30.83±1.67、39.47±3.03、56.87±2.50;在8Gy剂量点时,2组的CNE-2 G2期细胞比例均高达50%以上(66.97±1.47%与56.87±2.50%)。G2期细胞比例随照射剂量的增加而逐渐增加;在相同剂量点,模拟IMRT组G 2期细胞比例低于常规照射组。
2)常规照射组:S期细胞比例37.50±0.20、26.47±0.97、19.23±0.97、13.67±0.73;模拟IMRT组:S期细胞比例分别为39.73±0.47、32.43±1.03、26.07±2.77、16.87±2.33。S期细胞比例随照射剂量的增加而逐渐减少;在相同剂量点,模拟IMRT组的S期细胞比例高于常规照射组。
3)常规照射组:G1期细胞比例分别为35.73±0.23、35.20±0.80、34.20±0.50、19.37±0.73;模拟IMRT组:G1期细胞比例分别为39.20±0.40、36.73±0.63、34.47±0.33、26.27±0.27。G1期细胞比例随照射剂量的增加无明显变化;在相同剂量点,模拟IMRT组的G1期细胞比例略高于常规照射组。
4.流式细胞术检测细胞凋亡比例及存活比例(%):CNE-2在2、4、6、8Gy剂量点
1)常规照射组:早期凋亡比例分别为13.67±1.63、21.07±1.73、28.87±3.33、16.47±1.83;模拟IMRT组:早期凋亡比例分别为10.60±1.20、15.77±0.43、21.30±2.10、29.97±4.47;2Gy、4Gy、6Gy三个照射剂量点,早期凋亡比例随照射剂量的增加而逐渐增加;照射剂量为8Gy时,随剂量的增加,常规照射组早期凋亡比例不再增加反而下降;在相同剂量点,模拟IMRT组的早期凋亡比例低于常规照射组(8Gy除外)。
2)常规照射组:晚期凋亡比例分别为3.33±0.67、10.57±1.73、25.10±3.40、70.20±2.90;模拟IMRT组:晚期凋亡比例分别为1.80±0.90、7.13±1.37、21.77±2.47、59.37±3.67。晚期凋亡比例随照射剂量的增加成倍增加;在相同剂量点,模拟IMRT组的晚期凋亡比例低于常规照射组。
3)常规照射组:存活比例分别为82.83±1.67、47.40±4.90、21.73±6.93、5.13±1.37;模拟IMRT组:存活比例分别为87.40±2.10、54.70±3.50、27.80±5.30、7.57±1.77。细胞存活比例随照射剂量的增加而降低;在相同剂量点,模拟IMRT组的存活比例高于常规照射组。
5.RT-PCR、Western blotting方法检测CNE-2 Ku80、ATM的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组:Ku80的转录水平分别为0.588±0.131、0.929±0.125、0.840±0.084、0.775±0.084;模拟IMRT组:Ku80的转录水平分别为0.730±0.097、1.074±0.104、0.961±0.076、0.911±0.071;各组不同剂量点之间Ku80的转录水平差异均有统计学意义(P均=0.000);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,4个剂量点Ku80的转录水平差异均有统计学意义(P均<0.05);接受照射后CNE-2 Ku80转录水平升高,模拟IMRT组Ku80的转录水平更高(P均=0.000),在4Gy剂量点时2组细胞Ku80的转录水平到达峰值,随后表达均下降。
2)常规照射组:ATM转录水平分别为0.908±0.110、1.057±0.313、0.923±0.133、0.823±0.075;模拟IMRT组:ATM的转录水平分别为0.732±0.189、0.903±0.181、0.871±0.067、0.775±0.130;接受照射后,与空白对照比较,2组CNE-2 ATM转录水平均上调(P均<0.005);各组不同剂量点之间,ATM的转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,ATM的转录水平差异均无统计学意义(P均>0.05)。
Western blotting方法检测CNE-2 Ku80、ATM的蛋白表达均得到相似结果。
6.PT-PCR、Western blotting方法检测CNE-2 Cyclin B1、Cyclin D1的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组:Cyclin B1的转录水平分别为0.745±0.068、0.624±0.100、0.518±0.054、0.428±0.038;模拟IMRT组:Cyclin B1的转录水平分别为0.881±0.075、0.711±0.054、0.617±0.061、0.528±0.046;2组Cyclin B1的转录水平随照射剂量的增加而降低;各组不同剂量点之间,Cyclin B1的转录水平差异均有统计学意义(P均=0.000);且在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Cyclin B1的转录水平差异均有统计学意义(P均<0.05),模拟IMRT组Cyclin B1的转录水平高于常规照射组。
2)常规照射组:Cyclin D1的转录水平分别为0.857±0.090、0.810±0.327、0.798±0.303、0.802±0.038;模拟IMRT组:Cyclin D1的转录水平分别为0.822±0.063、0.701±0.213、0.812±0.093、0.801±0.064,各组不同剂量点之间转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Cyclin D1的转录水平差异均无统计学意义(P均>0.05)。
Western blotting方法检测CNE-2 Cyclin B1、Cyclin D1的蛋白表达均得到相似结果。
7.PT-PCR、Western blotting方法检测CNE-2 Bcl2、Bax的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组: Bcl2的转录水平分别为0.298±0.029、0.308±0.024、0.290±0.033、0.273±0.025;模拟IMRT组:Bcl2的转录水平分别为0.313±0.030、0.297±0.028、0.294±0.021、0.293±0.025;各组不同剂量点之间,转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Bcl2的转录水平差异均无统计学意义(P均>0.05)。
2)常规照射组:Bax的转录水平分别为0.618±0.061、0.706±0.032、0.817±0.064、0.915±0.076;模拟IMRT组:Bax的转录水平分别为0.513±0.051、0.606±0.087、0.662±0.132、0.721±0.086;2组Bax的转录水平随照射剂量的增加而升高;各组不同剂量点之间,Bax的转录水平差异均有统计学意义(P均=0.000);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Bax的转录水平差异均有统计学意义(P均<0.05),模拟IMRT组Bax的转录水平低于常规照射组。
Western blotting方法检测CNE-2 Bcl2、Bax的蛋白表达均得到相似结果。
结论:
1.照射时间延长,CNE-2存活分数增加,提示对肿瘤细胞的杀灭减少,在此期间可能发生亚致死性损伤修复,放射敏感性下降,放射生物效应降低。
2.电离辐射诱导CNE-2 G2期阻滞,其阻滞作用随剂量增加而增加;模拟IMRT照射时间的延长,对G2期细胞阻滞作用减弱。电离辐射诱导CNE-2凋亡,细胞凋亡比例随照射剂量的增加而增加,细胞存活比例随照射剂量的增加而降低。模拟IMRT照射时间延长,CNE-2凋亡比例下降及存活比例均上升,导致辐射生物效应降低。流式细胞术较好地反映了辐射对CNE-2细胞周期分布及凋亡比例的影响。
3.应用RT-PCR、Western blotting方法检测ATM、Ku80、Cyclin D1、Cyclin B1、Bcl2及Bax的转录水平及蛋白表达,并计算Bcl2/Bax的比值,可能有助于评价CNE-2放射生物效应的改变。IMRT时间延长,可能有利于SLDR,降低放射敏感性。DNA损伤修复相关因子Ku80、ATM,细胞周期素相关因子Cyclin D1、Cyclin B1,凋亡相关因子Bcl2、Bax的表达,可能部分预测辐射生物效应的变化。与常规放疗相比,IMRT这种高剂量率、多间歇、照射时间延长的照射模式有其独特的辐射生物效应,需要更进一步的研究。
Backgrounds & Objectives:
Nasopharyngeal carcinoma (NPC) is one of the most common human cancers, and is highly prevalent in Southern China. Radiotherapy is the primary treatment of NPC. Intensity-modulated radiation therapy (IMRT) has become common as a new radiotherapy technique for treatment of malignancies. Compared with conventional 3D conformal radiotherapy (3D-CRT), Intensity-modulated radiation therapy allows greater dose conformity to the tumor target and normal tissues sparing; meanwhile, IMRT optimizes dose distribution of radiotherapy, which thereby could increase the dose of the target tissues and decrease the dose of the surrounding normal tissues at risk. All these technical innovations have led on the one hand to delivering a much higher dose to the target volumes, thus possibly increasing local tumor control, while on the other hand minimizing the undue dose delivered to the surrounding normal tissues, thus possibly decreasing treatment morbidity. IMRT has obvious dosimetric superiority. Over the past few years, IMRT appears to be more and more commonly used for routine treatment, especially in head and neck (HN) malignancies, prostate cancer, breast cancer and lung cancer. However, only a few randomized trials have demonstrated its superiority over conventional treatments. This technique often requires 15～30 min or a longer time in one treatment session for precise positioning of patient. Several studies suggested that the radiobiological effectiveness of IMRT that require considerably long beam interruption might be less than that of continuous irradiation with the same dose owing to the recovery from sublethal damage in tumor cells. It is known that sublethal damage repair (SLDR), cell cycle and apoptosis influence the radiosensitivity of tumor cells. To our knowledge, however, no systematic research has been carried out regarding the influence of IMRT on radiosensitivity、apoptosis and cell cycle and radiosensitivity-related genes expression in cultured tumor cells.
Methods:
Radiosensitivity was analyzed by Courtenay assay. Cell growth inhibition was measured by MTT. Apoptosis and cell cycle were analyzed by flow cytometry. RT-PCR was used to detect mRNA expressions of damage repair -related genes: Ku80、ATM; Cell cycle regulation genes: Cyclin D1、Cyclin B1.Apoptotic regulation genes: Bcl2、Bax; Western blotting was used to analyze protein expression.
Results:
1.Courtenay assay
1)α/βof CNE-2 was 13.177Gy.when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy, Surviving Fractions (SF) of convention radiation (CR) group were 0.2253±0.0177、0.013±0.002、0.0026±0.0006 and 0.0002±0.0001. Surviving Fractions (SF) of Simulation IMRT (SIMRT) group were 0.3353±0.0167, 0.0607±0.0093, 0.0069±0.0009 and 0.0006±0.0003, respectively. Compared with SIMRT group, SF of convention radiation group was lower in every dose point.
2) Fitting cell survival curve by Linear quadratic equation and Multi-target one-shot model, the values ofα、β、N、D0、Dq of CR group were 0.674,8、0.051,2、1.890,0、0.885,0 and 0.563 0. The values ofα、β、N、D0、Dq of SIMRT group were 0.537,7、0.026,8、2.610,0、0.986,0 and 0.946,0, respectively; andαCR>αSIMRT,βCR>βSIMRT, NCR 2.MTT: when we delivered 2Gy、4Gy、6Gy、8Gy upon them, cell proliferation rates of CR group were0.598,7±0.021,7、0.455,7±0.053,7、0.235,3±0.045,3、0.056,7±0.018,3. Cell proliferation rates of SIMRT group were 0.682,0±0.055,0、0.528,3±0.074,3、0.322,3±0.002,0、0.091,7±0.022,3, respectively.
3.Flow cytometry for cell cycle: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) G2 phases of CR group were26.77±0.43、38.33±1.77、46.57±1.43、66.97±1.47. G2 phases of SIMRT group were 21.07±0.87、30.83±1.67、39.47±3.03、56.87±2.50. The rate G2 phase was increasing with the radiation dose rised. Compared with SIMRT group, the rate G2 phase of convention radiation group was higher in every dose point. In 8Gy, the rate G2 phase of both CR group and SIMRT group was over 50% (66.97±1.47% vs 56.87±2.50%).
2) S phases of CR group were 37.50±0.20、26.47±0.97、19.23±0.97、13.67±0.73; S phases of SIMRT group were 39.73±0.47、32.43±1.03、26.07±2.77、16.87±2.33, respectively. The rate of S phase was decreasing with the radiation dose rised. Compared with SIMRT group, the rate S phase of convention radiation group was lower in every dose point.
3) G1 phases of CR group were 35.73±0.23、35.20±0.80、34.20±0.50、19.37±0.73. G1 phases of SIMRT group were 39.20±0.40、36.73±0.63、34.47±0.33、26.27±0.27, respectively.The rate of G1 phase was decreasing with the radiation dose rised.Compared with SIMRT group, the rate S phase of CR group was relatively stable with the radiation dose rised.Compared with SIMRT group, the rate S phase of convention radiation group was a little lower in every dose point.
4.Flow cytometry for cell apoptosis: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) Early apoptosis of CR group were 13.67±1.63、21.07±1.73、28.87±3.33、16.47±1.83. Early apoptosis of SIMRT group were 10.60±1.20、15.77±0.43、21.30±2.10、29.97±4.47; respectively; From 2Gy to 6Gy, early apoptosis of both group increased, interestingly, when radiation doses upto 8Gy, early apoptosis of CR group decreased. Compared with SIMRT group, From 2Gy to 6Gy, early apoptosis of CR group was higher with the radiation dose rised.
2) Late apoptosis of CR group were 3.33±0.67、10.57±1.73、25.10±3.40、70.20±2.90. Early apoptosis of SIMRT group were 1.80±0.90、7.13±1.37、21.77±2.47、59.37±3.67; respectively. From 2Gy to 8Gy, late apoptosis of both group increased.Compared with SIMRT group, early apoptosis of CR group was higher in every dose point.
3) The rates of viable cells of CR group were 82.83±1.67、47.40±4.90、21.73±6.93、5.13±1.37.The rates of viable cells of SIMRT group were 87.40±2.10、54.70±3.50、27.80±5.30、7.57±1.77; respectively. From 2Gy to 8Gy, the rates of viable cells of both group decreased. Compared with SIMRT group, the rates of viable cells of CR group was lower in every dose point.
5.RT-PCR and Western blotting were employed to detect the expression of Ku80、ATM. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Ku80 mRNA level expressions of CR group were 0.588±0.131、0.929±0.125、0.840±0.084、0.775±0.084.The Ku80 mRNA level expressions of SIMRT group were 0.730±0.097、1.074±0.104、0.961±0.076、0.911±0.071, respectively. Compared with SIMRT group, the Ku80 mRNA level expressions of SIMRT group were lower in every dose point (P<0.05). And the Ku80 mRNA level expressions of both groups were highest in 4Gy. Western blotting showed the similar results on the protein level expressions.
2) The ATM mRNA level expressions of CR group were 0.908±0.110、1.057±0.313、0.923±0.133、0.823±0.075. The ATM mRNA level expressions of SIMRT group were 0.732±0.189、0.903±0.181、0.871±0.067、0.775±0.130, respectively.The ATM mRNA level expressions were up regulated after radiation (P<0.01). Compared with SIMRT group, the ATM mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
6.RT-PCR and Western blotting were employed to detect the expression of Cyclin B1、Cyclin D1. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Cyclin B1 mRNA level expressions of CR group were 0.745±0.068、0.624±0.100、0.518±0.054、0.428±0.038.The Cyclin B1 mRNA level expressions of SIMRT group were 0.881±0.075、0.711±0.054、0.617±0.061、0.528±0.046; respectively. Compared with SIMRT group, the Cyclin B1 mRNA level expressions of CR group were lower in every dose point (P<0.05). Western blotting showed the similar results on the protein level expressions.
2) The Cyclin D1 mRNA level expressions of CR group were 0.857±0.090、0.810±0.327、0.798±0.303、0.802±0.038.The Cyclin D1 mRNA level expressions of SIMRT group were 0.822±0.063、0.701±0.213、0.812±0.093、0.801±0.064, respectively. Compared with SIMRT group, the Cyclin D1 mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
7.RT-PCR and Western blotting were employed to detect the expression of Bcl2、Bax. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Bcl2 mRNA level expressions of CR group were 0.298±0.029、0.308±0.024、0.290±0.033、0.273±0.025. The Bcl2 mRNA level expressions of SIMRT group were 0.313±0.030、0.297±0.028、0.294±0.021、0.293±0.025; respectively. Compared with SIMRT group, the Bcl2 mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
2) The Bax mRNA level expressions of CR group were 0.618±0.061、0.706±0.032、0.817±0.064、0.915±0.076.The Bax mRNA level expressions of SIMRT group were 0.513±0.051、0.606±0.087、0.662±0.132、0.721±0.086, respectively. Compared with SIMRT group, the Bax mRNA level expressions of CR group is higher in every dose point (P<0.05). Western blotting showed the similar results on the protein level expressions.
Conclusions:
1.IMRT that require considerably long beam interruption may be one of the mechanisms responsible for altered radiosensitivity.
2.Radiation-induced G2 arrest correlated with radiation dose and IMRT that required considerably long beam interruption weaken the effect of G2 arrest. Radiation-induced early and late apoptosis ratios were increasing when radiation dose raised and IMRT that required considerably long beam interruption weaken the effect of apoptosis and increased the rate of viable cells.
3.Using RT-PCR and Western blotting to detect the expression of ATM、Ku80、Cyclin D1、Cyclin B1、Bcl2、Bax,and calculate the Bcl2/Bax ratio maybe a new approach to evaluate the altered IMRT radiobiological effect. And this unique radiobiological effect of IMRT is worthy of further research.
鼻咽癌是人类常见的恶性肿瘤之一,尤其在我国南方高发,放射治疗作为首选治疗。调强放射治疗(intensity-modulated radiation therapy IMRT)技术作为先进放疗技术的代表,突破了传统常规放疗的规则大野照射,以不规则的多个子野从多个角度在保护危及器官及正常组织的同时,最大限度的给予肿瘤区域以较高剂量照射;IMRT还可实现同时补量技术,在治疗次数相同的情况下,给不同的靶区不同剂量。以期提高局控率并减少周围正常组织损伤,因而成为临床肿瘤放射治疗走向精确定位、精确计划设计、精确治疗的标志。近年来,IMRT因其技术优势广泛应用于临床肿瘤放射治疗实践中,如头颈部肿瘤、前列腺癌、乳腺癌、肺癌等。IMRT在物理学上的优势是显而易见的。关于IMRT放疗近期疗效的报道很多,而且大多数结果尚属满意,但至今没有大范围的、有说服力的这种治疗改善了预后的资料。因此推测这一技术在在生物学上可能存在不足之处。因为治疗技术的复杂性,使在常规照射时一次性给予的剂量分成了多次给予,尤其是MLC静态IMRT技术大大延长了照射时间。常规2Gy的照射1～2min即可完成,而IMRT则常常需要20～40min。这样单位时间内肿瘤吸收剂量就大大降低,有人将这种情况称为“相对剂量率降低”。这种照射模式所致“相对剂量率降低是否影响肿瘤细胞的杀灭”已成为临床放射生物学的热点问题。多年来,人们应用细胞培养、免疫组化、分子生物学技术等对肿瘤细胞相关基因蛋白表达情况进行了研究,积累了大量资料。也有作者就离体细胞IMRT照射后,细胞存活曲线的变化进行过研究,从而推断IMRT照射时间延长,可能导致亚致死性损伤修复增加,放射生物效应降低,但其确切影响仍不清楚,未见其他方面深入的报道。放射治疗模式的改变是否会影响肿瘤细胞的生物效应尚未明确,是否要对IMRT照射模式进行剂量补偿亦尚未定论。文献报道,影响细胞放射敏感性的生物因素主要包括DNA损伤的修复、细胞周期、及细胞凋亡。因此本研究旨在通过给予人鼻咽低分化鳞癌细胞株(CNE-2)不同模式照射,探索IMRT治疗模式对CNE-2生物效应的影响。为今后IMRT在临床上的广泛应用,放疗剂量的调整,缩短照射时间,从而提高肿瘤局控率,进一步提高远期生存率,提供实验依据。并依据检测指标的变化,为患者制定个体化的放疗方案,如:确定分割剂量,选择照射时间,提供理论依据。
方法:
选取CNE-2为实验对象,分为空白对照、常规照射、模拟IMRT(按设计要求对各个照射剂量点进行照射,每个剂量点分5次照射,其间分别间隔8.0-8.5min, 35min完成)3组,分别给予6MV-X 2、4、6、8Gy4个剂量点的照射;1)运用克隆形成实验(courtenay assay),检测不同照射模式下CNE-2的存活分数; 2)运用四氮唑蓝法(MTT)进一步验证克隆形成实验的结果;3)运用流式细胞仪(FCM)检测不同照射模式下CNE-2的细胞周期分布及凋亡比例;4)应用RT-PCR及Western blotting方法,检测CNE-2在不同照射模式下,与DNA损伤修复相关的Ku、ATM转录水平及蛋白表达;检测与细胞周期调控相关的Cyclin B1、Cyclin D1的转录水平及蛋白表达,检测与细胞凋亡调节相关的Bcl2、Bax的转录水平及蛋白表达。
结果:
1.克隆形成检测细胞存活分数:
1)CNE-2α/β值为13.177Gy,在2、4、6、8Gy剂量点,常规照射组:SF值分别为0.225,3±0.017,7、0.013±0.002,0、0.002,6±0.000,6和0.0,002±0.000,1,模拟IMRT组:SF分别为0.335,3±0.016,7、0.060,7±0.009,3、0.006,9±0.000,9和0.000,6±0.0,003;模拟IMRT组的SF均高于常规照射组。
2)根据线性二次方程拟合的CNE-2细胞存活曲线,常规放疗组:α、β、N、D0、Dq值分别为0.674,8、0.051,2、1.890,0、0.885,0、0.563,0,模拟IMRT组:α、β、N、D0、Dq值分别为0.537,7、0.026,8、2.610,0、0.986,0和0.946,0;α_(常规)>α_(IMRT),β_(常规)>β_(IMRT),N_(常规)〈N_(IMRT),D_(0常规)
CNE-2在2、4、6、8Gy剂量点,常规照射组:细胞增殖比例分别为0.598,7±0.021,7、0.455,7±0.053,7、0.235,3±0.045,3、0.056,7±0.018,3;模拟IMRT组:细胞增殖比例分别为0.682±0.055,0、0.528,3±0.074,3、0.322,3±0.002,0、0.091,7±0.022,3;模拟IMRT组的增殖比例均高于常规照射组。
3.流式细胞术检测细胞周期分布(%):CNE-2在2、4、6、8Gy剂量点
1)常规照射组:G2期细胞比例分别为26.77±0.43、38.33±1.77、46.57±1.43、66.97±1.47;模拟IMRT组:G2期细胞比例分别为21.07±0.87、30.83±1.67、39.47±3.03、56.87±2.50;在8Gy剂量点时,2组的CNE-2 G2期细胞比例均高达50%以上(66.97±1.47%与56.87±2.50%)。G2期细胞比例随照射剂量的增加而逐渐增加;在相同剂量点,模拟IMRT组G 2期细胞比例低于常规照射组。
2)常规照射组:S期细胞比例37.50±0.20、26.47±0.97、19.23±0.97、13.67±0.73;模拟IMRT组:S期细胞比例分别为39.73±0.47、32.43±1.03、26.07±2.77、16.87±2.33。S期细胞比例随照射剂量的增加而逐渐减少;在相同剂量点,模拟IMRT组的S期细胞比例高于常规照射组。
3)常规照射组:G1期细胞比例分别为35.73±0.23、35.20±0.80、34.20±0.50、19.37±0.73;模拟IMRT组:G1期细胞比例分别为39.20±0.40、36.73±0.63、34.47±0.33、26.27±0.27。G1期细胞比例随照射剂量的增加无明显变化;在相同剂量点,模拟IMRT组的G1期细胞比例略高于常规照射组。
4.流式细胞术检测细胞凋亡比例及存活比例(%):CNE-2在2、4、6、8Gy剂量点
1)常规照射组:早期凋亡比例分别为13.67±1.63、21.07±1.73、28.87±3.33、16.47±1.83;模拟IMRT组:早期凋亡比例分别为10.60±1.20、15.77±0.43、21.30±2.10、29.97±4.47;2Gy、4Gy、6Gy三个照射剂量点,早期凋亡比例随照射剂量的增加而逐渐增加;照射剂量为8Gy时,随剂量的增加,常规照射组早期凋亡比例不再增加反而下降;在相同剂量点,模拟IMRT组的早期凋亡比例低于常规照射组(8Gy除外)。
2)常规照射组:晚期凋亡比例分别为3.33±0.67、10.57±1.73、25.10±3.40、70.20±2.90;模拟IMRT组:晚期凋亡比例分别为1.80±0.90、7.13±1.37、21.77±2.47、59.37±3.67。晚期凋亡比例随照射剂量的增加成倍增加;在相同剂量点,模拟IMRT组的晚期凋亡比例低于常规照射组。
3)常规照射组:存活比例分别为82.83±1.67、47.40±4.90、21.73±6.93、5.13±1.37;模拟IMRT组:存活比例分别为87.40±2.10、54.70±3.50、27.80±5.30、7.57±1.77。细胞存活比例随照射剂量的增加而降低;在相同剂量点,模拟IMRT组的存活比例高于常规照射组。
5.RT-PCR、Western blotting方法检测CNE-2 Ku80、ATM的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组:Ku80的转录水平分别为0.588±0.131、0.929±0.125、0.840±0.084、0.775±0.084;模拟IMRT组:Ku80的转录水平分别为0.730±0.097、1.074±0.104、0.961±0.076、0.911±0.071;各组不同剂量点之间Ku80的转录水平差异均有统计学意义(P均=0.000);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,4个剂量点Ku80的转录水平差异均有统计学意义(P均<0.05);接受照射后CNE-2 Ku80转录水平升高,模拟IMRT组Ku80的转录水平更高(P均=0.000),在4Gy剂量点时2组细胞Ku80的转录水平到达峰值,随后表达均下降。
2)常规照射组:ATM转录水平分别为0.908±0.110、1.057±0.313、0.923±0.133、0.823±0.075;模拟IMRT组:ATM的转录水平分别为0.732±0.189、0.903±0.181、0.871±0.067、0.775±0.130;接受照射后,与空白对照比较,2组CNE-2 ATM转录水平均上调(P均<0.005);各组不同剂量点之间,ATM的转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,ATM的转录水平差异均无统计学意义(P均>0.05)。
Western blotting方法检测CNE-2 Ku80、ATM的蛋白表达均得到相似结果。
6.PT-PCR、Western blotting方法检测CNE-2 Cyclin B1、Cyclin D1的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组:Cyclin B1的转录水平分别为0.745±0.068、0.624±0.100、0.518±0.054、0.428±0.038;模拟IMRT组:Cyclin B1的转录水平分别为0.881±0.075、0.711±0.054、0.617±0.061、0.528±0.046;2组Cyclin B1的转录水平随照射剂量的增加而降低;各组不同剂量点之间,Cyclin B1的转录水平差异均有统计学意义(P均=0.000);且在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Cyclin B1的转录水平差异均有统计学意义(P均<0.05),模拟IMRT组Cyclin B1的转录水平高于常规照射组。
2)常规照射组:Cyclin D1的转录水平分别为0.857±0.090、0.810±0.327、0.798±0.303、0.802±0.038;模拟IMRT组:Cyclin D1的转录水平分别为0.822±0.063、0.701±0.213、0.812±0.093、0.801±0.064,各组不同剂量点之间转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Cyclin D1的转录水平差异均无统计学意义(P均>0.05)。
Western blotting方法检测CNE-2 Cyclin B1、Cyclin D1的蛋白表达均得到相似结果。
7.PT-PCR、Western blotting方法检测CNE-2 Bcl2、Bax的转录水平及蛋白表达:CNE-2在2、4、6、8Gy剂量点
1)常规照射组: Bcl2的转录水平分别为0.298±0.029、0.308±0.024、0.290±0.033、0.273±0.025;模拟IMRT组:Bcl2的转录水平分别为0.313±0.030、0.297±0.028、0.294±0.021、0.293±0.025;各组不同剂量点之间,转录水平差异均无统计学意义(P均>0.05);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Bcl2的转录水平差异均无统计学意义(P均>0.05)。
2)常规照射组:Bax的转录水平分别为0.618±0.061、0.706±0.032、0.817±0.064、0.915±0.076;模拟IMRT组:Bax的转录水平分别为0.513±0.051、0.606±0.087、0.662±0.132、0.721±0.086;2组Bax的转录水平随照射剂量的增加而升高;各组不同剂量点之间,Bax的转录水平差异均有统计学意义(P均=0.000);在相同剂量点,常规照射组与模拟IMRT组LSD法两两比较,Bax的转录水平差异均有统计学意义(P均<0.05),模拟IMRT组Bax的转录水平低于常规照射组。
Western blotting方法检测CNE-2 Bcl2、Bax的蛋白表达均得到相似结果。
结论:
1.照射时间延长,CNE-2存活分数增加,提示对肿瘤细胞的杀灭减少,在此期间可能发生亚致死性损伤修复,放射敏感性下降,放射生物效应降低。
2.电离辐射诱导CNE-2 G2期阻滞,其阻滞作用随剂量增加而增加;模拟IMRT照射时间的延长,对G2期细胞阻滞作用减弱。电离辐射诱导CNE-2凋亡,细胞凋亡比例随照射剂量的增加而增加,细胞存活比例随照射剂量的增加而降低。模拟IMRT照射时间延长,CNE-2凋亡比例下降及存活比例均上升,导致辐射生物效应降低。流式细胞术较好地反映了辐射对CNE-2细胞周期分布及凋亡比例的影响。
3.应用RT-PCR、Western blotting方法检测ATM、Ku80、Cyclin D1、Cyclin B1、Bcl2及Bax的转录水平及蛋白表达,并计算Bcl2/Bax的比值,可能有助于评价CNE-2放射生物效应的改变。IMRT时间延长,可能有利于SLDR,降低放射敏感性。DNA损伤修复相关因子Ku80、ATM,细胞周期素相关因子Cyclin D1、Cyclin B1,凋亡相关因子Bcl2、Bax的表达,可能部分预测辐射生物效应的变化。与常规放疗相比,IMRT这种高剂量率、多间歇、照射时间延长的照射模式有其独特的辐射生物效应,需要更进一步的研究。
Backgrounds & Objectives:
Nasopharyngeal carcinoma (NPC) is one of the most common human cancers, and is highly prevalent in Southern China. Radiotherapy is the primary treatment of NPC. Intensity-modulated radiation therapy (IMRT) has become common as a new radiotherapy technique for treatment of malignancies. Compared with conventional 3D conformal radiotherapy (3D-CRT), Intensity-modulated radiation therapy allows greater dose conformity to the tumor target and normal tissues sparing; meanwhile, IMRT optimizes dose distribution of radiotherapy, which thereby could increase the dose of the target tissues and decrease the dose of the surrounding normal tissues at risk. All these technical innovations have led on the one hand to delivering a much higher dose to the target volumes, thus possibly increasing local tumor control, while on the other hand minimizing the undue dose delivered to the surrounding normal tissues, thus possibly decreasing treatment morbidity. IMRT has obvious dosimetric superiority. Over the past few years, IMRT appears to be more and more commonly used for routine treatment, especially in head and neck (HN) malignancies, prostate cancer, breast cancer and lung cancer. However, only a few randomized trials have demonstrated its superiority over conventional treatments. This technique often requires 15～30 min or a longer time in one treatment session for precise positioning of patient. Several studies suggested that the radiobiological effectiveness of IMRT that require considerably long beam interruption might be less than that of continuous irradiation with the same dose owing to the recovery from sublethal damage in tumor cells. It is known that sublethal damage repair (SLDR), cell cycle and apoptosis influence the radiosensitivity of tumor cells. To our knowledge, however, no systematic research has been carried out regarding the influence of IMRT on radiosensitivity、apoptosis and cell cycle and radiosensitivity-related genes expression in cultured tumor cells.
Methods:
Radiosensitivity was analyzed by Courtenay assay. Cell growth inhibition was measured by MTT. Apoptosis and cell cycle were analyzed by flow cytometry. RT-PCR was used to detect mRNA expressions of damage repair -related genes: Ku80、ATM; Cell cycle regulation genes: Cyclin D1、Cyclin B1.Apoptotic regulation genes: Bcl2、Bax; Western blotting was used to analyze protein expression.
Results:
1.Courtenay assay
1)α/βof CNE-2 was 13.177Gy.when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy, Surviving Fractions (SF) of convention radiation (CR) group were 0.2253±0.0177、0.013±0.002、0.0026±0.0006 and 0.0002±0.0001. Surviving Fractions (SF) of Simulation IMRT (SIMRT) group were 0.3353±0.0167, 0.0607±0.0093, 0.0069±0.0009 and 0.0006±0.0003, respectively. Compared with SIMRT group, SF of convention radiation group was lower in every dose point.
2) Fitting cell survival curve by Linear quadratic equation and Multi-target one-shot model, the values ofα、β、N、D0、Dq of CR group were 0.674,8、0.051,2、1.890,0、0.885,0 and 0.563 0. The values ofα、β、N、D0、Dq of SIMRT group were 0.537,7、0.026,8、2.610,0、0.986,0 and 0.946,0, respectively; andαCR>αSIMRT,βCR>βSIMRT, NCR
3.Flow cytometry for cell cycle: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) G2 phases of CR group were26.77±0.43、38.33±1.77、46.57±1.43、66.97±1.47. G2 phases of SIMRT group were 21.07±0.87、30.83±1.67、39.47±3.03、56.87±2.50. The rate G2 phase was increasing with the radiation dose rised. Compared with SIMRT group, the rate G2 phase of convention radiation group was higher in every dose point. In 8Gy, the rate G2 phase of both CR group and SIMRT group was over 50% (66.97±1.47% vs 56.87±2.50%).
2) S phases of CR group were 37.50±0.20、26.47±0.97、19.23±0.97、13.67±0.73; S phases of SIMRT group were 39.73±0.47、32.43±1.03、26.07±2.77、16.87±2.33, respectively. The rate of S phase was decreasing with the radiation dose rised. Compared with SIMRT group, the rate S phase of convention radiation group was lower in every dose point.
3) G1 phases of CR group were 35.73±0.23、35.20±0.80、34.20±0.50、19.37±0.73. G1 phases of SIMRT group were 39.20±0.40、36.73±0.63、34.47±0.33、26.27±0.27, respectively.The rate of G1 phase was decreasing with the radiation dose rised.Compared with SIMRT group, the rate S phase of CR group was relatively stable with the radiation dose rised.Compared with SIMRT group, the rate S phase of convention radiation group was a little lower in every dose point.
4.Flow cytometry for cell apoptosis: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) Early apoptosis of CR group were 13.67±1.63、21.07±1.73、28.87±3.33、16.47±1.83. Early apoptosis of SIMRT group were 10.60±1.20、15.77±0.43、21.30±2.10、29.97±4.47; respectively; From 2Gy to 6Gy, early apoptosis of both group increased, interestingly, when radiation doses upto 8Gy, early apoptosis of CR group decreased. Compared with SIMRT group, From 2Gy to 6Gy, early apoptosis of CR group was higher with the radiation dose rised.
2) Late apoptosis of CR group were 3.33±0.67、10.57±1.73、25.10±3.40、70.20±2.90. Early apoptosis of SIMRT group were 1.80±0.90、7.13±1.37、21.77±2.47、59.37±3.67; respectively. From 2Gy to 8Gy, late apoptosis of both group increased.Compared with SIMRT group, early apoptosis of CR group was higher in every dose point.
3) The rates of viable cells of CR group were 82.83±1.67、47.40±4.90、21.73±6.93、5.13±1.37.The rates of viable cells of SIMRT group were 87.40±2.10、54.70±3.50、27.80±5.30、7.57±1.77; respectively. From 2Gy to 8Gy, the rates of viable cells of both group decreased. Compared with SIMRT group, the rates of viable cells of CR group was lower in every dose point.
5.RT-PCR and Western blotting were employed to detect the expression of Ku80、ATM. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Ku80 mRNA level expressions of CR group were 0.588±0.131、0.929±0.125、0.840±0.084、0.775±0.084.The Ku80 mRNA level expressions of SIMRT group were 0.730±0.097、1.074±0.104、0.961±0.076、0.911±0.071, respectively. Compared with SIMRT group, the Ku80 mRNA level expressions of SIMRT group were lower in every dose point (P<0.05). And the Ku80 mRNA level expressions of both groups were highest in 4Gy. Western blotting showed the similar results on the protein level expressions.
2) The ATM mRNA level expressions of CR group were 0.908±0.110、1.057±0.313、0.923±0.133、0.823±0.075. The ATM mRNA level expressions of SIMRT group were 0.732±0.189、0.903±0.181、0.871±0.067、0.775±0.130, respectively.The ATM mRNA level expressions were up regulated after radiation (P<0.01). Compared with SIMRT group, the ATM mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
6.RT-PCR and Western blotting were employed to detect the expression of Cyclin B1、Cyclin D1. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Cyclin B1 mRNA level expressions of CR group were 0.745±0.068、0.624±0.100、0.518±0.054、0.428±0.038.The Cyclin B1 mRNA level expressions of SIMRT group were 0.881±0.075、0.711±0.054、0.617±0.061、0.528±0.046; respectively. Compared with SIMRT group, the Cyclin B1 mRNA level expressions of CR group were lower in every dose point (P<0.05). Western blotting showed the similar results on the protein level expressions.
2) The Cyclin D1 mRNA level expressions of CR group were 0.857±0.090、0.810±0.327、0.798±0.303、0.802±0.038.The Cyclin D1 mRNA level expressions of SIMRT group were 0.822±0.063、0.701±0.213、0.812±0.093、0.801±0.064, respectively. Compared with SIMRT group, the Cyclin D1 mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
7.RT-PCR and Western blotting were employed to detect the expression of Bcl2、Bax. RT-PCR results showed: when we delivered 4 different radiation doses including 2Gy、4Gy、6Gy、8Gy
1) The Bcl2 mRNA level expressions of CR group were 0.298±0.029、0.308±0.024、0.290±0.033、0.273±0.025. The Bcl2 mRNA level expressions of SIMRT group were 0.313±0.030、0.297±0.028、0.294±0.021、0.293±0.025; respectively. Compared with SIMRT group, the Bcl2 mRNA level expressions of CR group had no significant difference in every dose point (P>0.05). Western blotting showed the similar results on the protein level expressions.
2) The Bax mRNA level expressions of CR group were 0.618±0.061、0.706±0.032、0.817±0.064、0.915±0.076.The Bax mRNA level expressions of SIMRT group were 0.513±0.051、0.606±0.087、0.662±0.132、0.721±0.086, respectively. Compared with SIMRT group, the Bax mRNA level expressions of CR group is higher in every dose point (P<0.05). Western blotting showed the similar results on the protein level expressions.
Conclusions:
1.IMRT that require considerably long beam interruption may be one of the mechanisms responsible for altered radiosensitivity.
2.Radiation-induced G2 arrest correlated with radiation dose and IMRT that required considerably long beam interruption weaken the effect of G2 arrest. Radiation-induced early and late apoptosis ratios were increasing when radiation dose raised and IMRT that required considerably long beam interruption weaken the effect of apoptosis and increased the rate of viable cells.
3.Using RT-PCR and Western blotting to detect the expression of ATM、Ku80、Cyclin D1、Cyclin B1、Bcl2、Bax,and calculate the Bcl2/Bax ratio maybe a new approach to evaluate the altered IMRT radiobiological effect. And this unique radiobiological effect of IMRT is worthy of further research.
引文
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