时间:2024-09-03
张 静,周子娇
1. 唐山市人民医院肿瘤内科,河北 唐山063001; 2. 唐山市丰南区中医院内一科
替吉奥治疗胃癌的临床疗效与外周血内DPD mRNA和 TS mRNA表达水平的相关性
张 静1,周子娇2
1. 唐山市人民医院肿瘤内科,河北 唐山063001; 2. 唐山市丰南区中医院内一科
目的 分析替吉奥(S-1)治疗胃癌的临床疗效与外周血内二氢嘧啶脱氢酶(Dihydropyrimidine dehydrogenase, DPD)mRNA和胸苷酸合成酶(Thymidine synthetase, TS)mRNA表达水平的相关性。方法 选取唐山市人民医院2013年3月-2014年3月接受含S-1方案治疗的75例胃癌患者为研究对象,并进行前瞻性分析。患者化疗前抽取空腹静脉血7 ml,并检测其DPD mRNA、TS mRNA表达水平。结果 Lauren分型为肠型患者的DPD mRNA高表达率高于弥漫型患者;有远处转移患者的TS mRNA高表达率高于无远处转移者(P<0.05)。疗效判定为进展(PD)的患者,DPD、TS mRNA表达水平高于部分缓解(PR)、稳定(SD)患者;PR患者外周血DPD、TS mRNA表达水平低于SD患者(P<0.05)。DPD mRNA、TS mRNA表达与临床疗效均呈负相关(r=-0.713,r=-0.735,P<0.05)。不同毒副作用分级患者外周血DPD mRNA与TS mRNA表达比较,差异无统计学意义(P>0.05)。外周血DPD mRNA及TS mRNA高表达患者OS低于低表达患者(P<0.05)。结论 根据患者外周血DPD mRNA和TS mRNA表达水平可早期评估患者预后及治疗效果,为胃癌患者生存质量的改善奠定基础。
替吉奥;胃癌;疗效;二氢嘧啶脱氢酶;胸苷酸合成酶;相关性
早期诊断与及时实施根治性切除手术是保证胃癌患者生存质量的关键,但目前60%~80%的胃癌患者确诊时已进入进展期或转移期,失去了手术治疗的机会,仅能接受姑息性化疗[1]。替吉奥(S-1)是一种新型口服氟尿嘧啶类复方制剂,较传统胃癌化疗药物5-氟尿嘧啶(5-Fu)而言,该药疗效更佳且毒副作用更小,在胃癌的临床治疗中得到了一定范围的应用。但多数研究均发现,相同病理分型、临床分期及治疗方案的患者,其疗效与生存质量存在显著性差异,因此,明确这一差异的根源是指导个体化治疗、提高治疗效果的关键[2]。二氢嘧啶脱氢酶(Dihydropyrimidine dehydrogenase, DPD)和胸苷酸合成酶(Thymidine synthetase, TS)是5-Fu代谢过程中的关键酶,近年来在胃癌化疗治疗敏感性分析中得到了广泛关注[3]。本研究对75例胃癌患者外周血内DPD mRNA和TS mRNA表达水平进行了检测,分析其对S-1治疗效果的影响。
1.1 病例资料 收集唐山市人民医院2013年3月-2014年3月接受含S-1治疗方案的75例胃癌患者为研究对象,进行前瞻性分析。其中男49例,女26例,年龄42~79岁,平均年龄(59.71±8.37)岁。本研究经唐山市人民医院医学伦理委员会批准,患者均知情同意并签署知情同意书。
1.2 选取标准及排除标准 选取标准:(1)经组织学检查或细胞学检查确诊复发或转移性胃癌,无手术指征[4]。(2)年龄18~80岁,自愿接受S-1方案化疗。(3)体力状况Karnofsky评分(KPS评分)≥70分,预期生存期≥3个月。(4)无抗肿瘤治疗史或距离上次化疗>6个月、距离上次放疗>3个月。(5)肿瘤可测量病灶≥1个。排除标准:(1)入院白细胞(WBC)<4×109/L、中性粒细胞绝对数(ANC)<1.5×109/L、血红蛋白<100 g/L或血小板(PLT)<100×109/L。(2)血清胆红素高于正常上限。(3)若未合并肝转移,血清转氨酶>正常上限2.5倍,若合并肝转移,血清转氨酶>正常上限5倍。(4)尿素氮>正常上限1.25倍。(5)合并其他化疗禁忌证。
1.3 研究方法
1.3.1 治疗方案:患者均在常规止吐、保肝、水化、抑酸、止泻、预防过敏、营养支持、抗贫血、保护免疫功能等治疗的基础上加用S-1方案化疗,化疗方案[5]:S-1(江苏恒瑞医药股份有限公司,国药准字H20113281,规格20 mg×42 粒)口服治疗,2次/d,每日总剂量80 mg/m2,d1~d14,21 d为1个周期;顺铂(齐鲁制药有限公司,国药准字H37021358,规格10 mg)静脉滴注,剂量75 mg/m2,d1,21 d为1个周期。每2个周期实施疗效评价1次,根据疗效评定结果调整治疗方案。
1.3.2 观察指标:(1)疗效评价[6]:参照实体瘤疗效评价标准(RECIST v1.1)对患者治疗2个周期后的临床疗效进行评价:部分缓解(PR):病灶长径之和较治疗前减少≥30%;进展(PD):病灶长径之和较治疗前增加≥20%或出现新病灶;稳定(SD):病灶长径较治疗前减少<30%或增加<20%。(2)毒副作用观察:依据抗癌药物常见毒副作用分级标准对患者治疗期间毒副作用进行观察[7],包括WBC减少、PLT减少、血红蛋白下降、恶心呕吐、腹泻、口腔黏膜炎等,毒副作用分级0~Ⅲ级,分级越高毒副作用越严重。(3)外周血DPD mRNA和TS mRNA表达水平检测:抽取患者化疗前空腹肘静脉血7 ml,置于二钠EDTA抗凝管中,抽提mRNA统一保存于-80 ℃冰箱中待测。使用逆转录聚合酶链式反应(RT-PCR)检测mRNA,应用Quantity One软件(美国Bio-rad公司)对mRNA相对表达量进行分析[8]。以DPD mRNA>2.53、TS mRNA>0.636为高表达[9],比较不同临床病理特征、不同临床疗效、不同毒副反应分级患者外周血DPD mRNA和TS mRNA表达水平,并分析其与患者临床疗效的相关性。(4)生存状况分析:采用电话随访、门诊随诊等形式,对患者进行为期2年的随访,对其生存情况进行观察,总生存期(OS)定义为自患者入组时至全因死亡时间,应用Kaplan-Meier法绘制生存曲线,比较不同DPD mRNA、TS mRNA表达水平患者化疗后生存曲线的区别。
2.1 临床病理特征Lauren分型为肠型患者,DPDmRNA高表达率显著高于弥漫型,有远处转移患者,其TSmRNA高表达率显著高于无远处转移者,差异有统计学意义(P<0.05,见表1)。
表1 不同临床病理特征患者外周血DPD mRNA和TS mRNA表达比较[例数(%)]
Tab 1 Comparison of DPD mRNA and TS mRNA expressions in peripheral blood of patients with different clinical pathological characteristics [n(%)]
病理特征 例数DPDmRNA高表达χ2值P值TSmRNA高表达χ2值P值性别 男4919(38.78)0.245>0.0526(53.06)0.407>0.05 女269(34.62)15(57.70)年龄(岁) <604215(35.71)0.771>0.0525(59.52)0.359>0.05 ≥603313(39.39)16(48.48)肿瘤直径(cm) <53413(38.24)0.369>0.0518(52.94)0.441>0.05 ≥54115(36.59)10(24.39)浸润 T2114(36.36)0.582>0.056(54.55)0.187>0.05 T34011(27.50)19(47.50) T42413(54.17)16(66.67)Lauren分型 肠型3920(51.28)6.970<0.0525(64.10)0.260>0.05 弥漫型368(22.22)16(44.44)远处转移 无199(47.37)0.532>0.055(26.32)9.417<0.05 有5619(33.93)36(64.29)分化程度 高92(22.22)0.455>0.056(66.67)0.335>0.05 中226(27.27)11(50.00) 低4420(45.45)24(54.55)
2.2 临床疗效 PD患者的DPD mRNA和TS mRNA表达水平显著高于PR、SD患者,PR患者外周血DPD mRNA和TS mRNA表达水平显著低于SD患者,差异有统计学意义(P<0.05,见表2)。DPD mRNA及TS mRNA表达与临床疗效均呈显著负相关(r=-0.713,r=-0.735,P<0.05)。
2.3 毒副作用 不同毒副作用分级患者外周血DPD mRNA和TS mRNA表达比较,差异无统计学意义(P>0.05,见表3)。
分组例数DPDmRNATSmRNAPR组281.17±0.250.34±0.09SD组251.97±0.46∗0.63±0.15∗PD组224.39±0.74∗#0.96±0.20∗#F值6.9535.874P值>0.05>0.05
注:与PR比较,*P<0.05;与SD比较,#P<0.05。
毒副作用DPDmRNAP值TSmRNAP值WBC减少 0级2.13±0.84>0.050.69±0.11>0.05 Ⅰ级2.15±0.710.68±0.15 Ⅱ级2.19±0.650.71±0.23 Ⅲ级2.16±0.530.70±0.21PLT减少 0级2.20±0.47>0.050.68±0.14>0.05 Ⅰ级2.18±0.390.73±0.12 Ⅱ级2.19±0.480.70±0.13 Ⅲ级2.16±0.440.71±0.10
续表3
毒副作用DPDmRNAP值TSmRNAP值血红蛋白下降 0级2.25±0.63>0.050.69±0.15>0.05 Ⅰ级2.22±0.430.65±0.17 Ⅱ级2.17±0.910.71±0.23 Ⅲ级2.16±0.580.68±0.11恶心呕吐 0级2.09±0.94>0.050.70±0.14>0.05 Ⅰ级2.21±0.540.65±0.23 Ⅱ级2.13±0.650.68±0.15腹泻 0级2.14±0.71>0.050.68±0.13>0.05 Ⅰ级2.15±0.820.69±0.14 Ⅱ级2.19±0.950.69±0.15口腔黏膜炎 0级2.30±0.85>0.050.70±0.12>0.05 Ⅰ级2.26±0.410.66±0.17 Ⅱ级2.17±0.340.64±0.18
2.4 随访结果 外周血DPD mRNA和TS mRNA高表达患者平均OS分别为(5.67±0.72)个月、(7.86±0.80)个月,低于低表达患者的(8.07±0.88)个月、(13.33±0.73)个月,差异有统计学意义(P<0.05,见图1)。
图1 不同TS mRNA与DPD mRNA表达患者生存曲线
早期胃癌患者临床表现以恶心、呕吐为主,就诊率偏低,误诊、漏诊率较高,患者出现体质量减轻、疼痛症状时,病情往往已进展至中晚期,单纯手术治疗无法取得满意的疗效,选择合适的化疗方案控制肿瘤进展是为根治性手术奠定基础、改善患者生存质量的关键[10]。
5-Fu是胃癌化疗的首选基础药物,但近年来多数研究均表明5-Fu的远期安全性值得商榷,其对神经系统的副作用可导致小脑萎缩,关于5-Fu引发致死性消化道反应、血液系统毒性反应的报道屡见不鲜[11]。作为一种复方制剂,S-1的组分包括替加氟、吉美嘧啶与奥替拉西钾,其中替加氟是5-Fu的前体物质,具有较高的生物利用度,可在体内转化为5-Fu,其代谢产物5-Fu脱氧核苷酸(5-FuMP)具有较强的抗肿瘤作用;吉美嘧啶具有DPD拮抗功能,可抑制DPD对5-Fu的分解代谢作用,保证血浆及肿瘤组织中较高的5-Fu有效浓度,避免药效受影响[12];奥替拉西钾可拮抗乳清酸磷酸核糖基转移酶(ORPT),降低消化道中5-Fu向5-FuMP的转化功能,故可在一定程度上减轻S-1的消化道毒副反应风险。因此,较传统化疗药物而言,S-1具有给药方便、抗肿瘤作用强、消化道毒副作用小等优势,已有大量研究证实S-1在恶性肿瘤治疗中发挥的可靠疗效[13]。
但在S-1的临床实际应用中,多数学者均发现,相同肿瘤类型、临床分期、病理类型患者在接受相同方案化疗后,其临床疗效与生存质量往往存在较大差异,而部分临床分期、病理类型存在差异的患者,其临床疗效可能相似[14]。明确这一现状的发生机制,是提高化疗治疗水平、指导个体化化疗的关键。本研究结果示,随着患者临床疗效的提高,其外周血DPD mRNA和TS mRNA表达水平均呈下降趋势,说明DPD、TS高表达可能预示着患者预后不良,同时,本研究Lauren分型为肠型患者,其DPD mRNA高表达率显著高于弥漫型,有远处转移患者,其TS mRNA高表达率显著高于无远处转移者,也印证了上述结论。TS被认为是5-Fu及其衍生物治疗恶性肿瘤的靶目标,故TS表达水平的升高表明患者肿瘤组织侵袭性上升,对5-Fu药物的敏感性下降,甚至出现继发性耐药[15]。DPD是嘧啶类分解代谢的起始和限速酶,其活性在肝脏中最高,而5-Fu进入体内后,约80%在肝脏组织中分解代谢,故DPD表达水平可直接影响5-Fu进入合成代谢和产生5-FuMP的量,过往研究证实,DPD高表达可增加5-Fu分解,在肿瘤耐药现象的发生中扮演重要角色[16]。在毒副作用、生存时间的比较中,可以发现,外周血内DPD mRNA和TS mRNA表达水平较高的患者,其OS显著降低,也说明两种酶在患者治疗效果及预后的改变中发挥着重要作用,但不会影响患者不良反应发生风险。
综上所述,DPD mRNA和TS mRNA表达水平较低的胃癌患者更易从S-1治疗中获益,生存时间更长。但关于DPD和TS影响患者预后的具体机制仍有待进一步探讨,从而为胃癌等恶性肿瘤的个体化治疗提供指导,为患者预后的改善奠定基础。
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(责任编辑:李 健)
The correlation of clinical efficacy of S-1 in treating gastric cancer with the expressions of DPD mRNA and TS mRNA in peripheral blood
ZHANG Jing1, ZHOU Zijiao2
1. Department of Oncology, People’s Hospital of Tangshan City, Tangshan 063001; 2. Department of NO.1 Internal Medicine, Hospital of Traditional Chinese Medicine in Fengnan District of Tangshan City, China
Objective To analyze the correlation of clinical efficacy S-1 in treating gastric cancer with the expressions of Dihydrogen Dihydropyrimidine dehydrogenase (PD) mRNA and Thymidine synthase (TS) mRNA in peripheral blood.Methods Seventy-five patients with gastric cancer who were treated with S-1 in People’s Hospital of Tangshan City from Mar.2013 to Mar.2014 were selected and analyzed prospectively.7 ml of fasting venous blood before chemotherapy was collected and the DPD mRNA and TS mRNA expression levels were detected.Results The high expression rate of DPD mRNA was higher than that of diffuse type, there was a higher expression rate of mRNA TS in the patients with distant metastasis than those without distant metastasis, and the difference was statistically significant (P<0.05). The DPD mRNA and TS mRNA expression levels of patients with progressive disease (PD) were significantly higher than those in partial remission (PR), stable (SD) patients. The serum DPD mRNA and TS mRNA expression levels in PR patients were significantly lower than those in SD patients, the difference was statistically significant (P<0.05). The DPD mRNA and TS mRNA expressions were negatively correlated with clinical efficacy (r=-0.713,r=-0.735,P< 0.05). There was no significant difference in the expressions of DPD mRNA and TS mRNA in peripheral blood of patients with different toxic and side effects (P>0.05). The DPD mRNA and TS mRNA patients with high expression of peripheral blood OS were significantly lower than those with low expression, and the difference was statistically significant (P<0.05).Conclusion According to the peripheral blood DPD mRNA and TS mRNA expression levels of early assessment of prognosis and therapeutic effect, for the improvement of quality of life in patients with gastric cancer lay the foundation.
S-1; Gastric cancer; Curative effect; Two hydrogen-induced dehydrogenase; Thymidine synthase; Correlation
张静,副主任医师,研究方向:肿瘤放化疗。E-mail:sdwxm7758@163.com
10.3969/j.issn.1006-5709.2016.11.011
R735.2
A
1006-5709(2016)11-1248-05
2016-04-21
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