TLR4-NFκB信号通路在顺铂致胃癌SGC-7901细胞凋亡中的作用

目的 探讨TLR4-NFκB信号通路在顺铂致胃癌细胞凋亡中的作用。方法 终浓度为10 μmol/L的顺铂处理SGC-7901细胞12 h后,Western blot检测SGC-7901细胞中TLR4和NFκB的表达情况。设计合成无义序列和TLR4 siRNA序列,分别转染至SGC-7901细胞,即无义序列转染组(Scramb-Anti-TLR4 group)和TLR4 siRNA序列转染组(Anti-TLR4 group)。顺铂处理后,Western blot检测细胞中TLR4、NFκB、Bax、Bcl-2、Activecaspase-3和GAPDH的表达,流式细胞术检测细胞凋亡和坏死。结果 顺铂处理后TLR4(t=14.070,P＜0.001)和NFκB(t=17.660,P＜0.001)的表达显著增加。与Scramb-Anti-TLR4组相比较,Anti-TLR4组在顺铂处理后TLR4(t=16.810,P＜0.001)和NFκB(t=15.040,P＜0.001)表达显著下降;Bax(t=17.870,P＜0.001)和Activecaspase-3(t=8.881,P＜0.001)表达显著升高,Bcl-2(t=17.300,P＜0.001)表达显著下降;细胞凋亡率(t=4.122,P＜0.001)和坏死率(t=9.367,P＜0.001)显著升高。结论 顺铂可以激活胃癌SGC-7901细胞的TLR4-NFκB信号通路,抑制TLR4-NFκB信号通路可以增强顺铂的致凋亡效应。     

siRNA介导RRM2基因沉默治疗人卵巢癌裸鼠移植瘤

目的 探讨siRNA沉默核糖核苷酸还原酶M2(RRM2)基因联合顺铂治疗人卵巢癌裸鼠移植瘤的可行性。 方法 常规体外培养人卵巢癌细胞株SKOV3,采用皮下注射法建立卵巢癌裸鼠皮下移植瘤模型,将24只荷瘤鼠随机分为对照组、顺铂组、siRNA组、siRNA联合顺铂组,每组6只,分组给药。观察肿瘤生长情况,测瘤体积并计算肿瘤生长抑制率。采用RT-PCR和免疫组织化学方法分别检测肿瘤组织中RRM2 mRNA及蛋白表达。 结果 对照组、siRNA组、顺铂组和siRNA联合顺铂组平均肿瘤体积分别为(358.28±46.40)、(261.38±52.49)、(261.65±31.97)、(189.37±41.67)mm³,单药作用后肿瘤体积差异有统计学意义(F_siRNA-RRM2=22.399,P_siRNA-RRM2<0.001;F_顺铂=22.254,P_顺铂<0.001);两药间无交互作用(F=0.474,P=0.499)。对照组、siRNA组、顺铂组和siRNA联合顺铂组肿瘤生长抑制率分别为0、36.39%、41.10%、64.33%。siRNA-RRM2与顺铂单药各自均能降低RRM2 mRNA表达水平(F_siRNA-RRM2=9.37,P_siRNA-RRM2=0.006;F顺铂=11.90,P顺铂=0.003)和蛋白表达水平(F_siRNA-RRM2=8.71,P_siRNA-RRM2=0.008;F顺铂=13.01,P顺铂=0.002);两药间无交互作用(F_{RRM2 mRNA}=3.93,P_{RRM2 mRNA}=0.061;F_RRM2蛋白=1.72,P_RRM2蛋白=0.204)。 结论 单用siRNA或联用顺铂均可有效抑制人卵巢癌裸鼠皮下移植瘤瘤体的生长,可能与其沉默RRM2基因表达有关,特异性沉默RRM2或可成为卵巢癌治疗的一个新思路。     

顺铂对雌性大鼠骨密度影响的实验研究

目的本文通过对去势雌性大鼠的动物实验研究，观察顺铂对骨代谢、骨密度的影响，并探讨其可能机制。方法将三月龄雌性SD大鼠30只，随机分为对照组和化疗组，每组15只。各组大鼠均用1％戊巴比妥钠腹腔内麻醉，行双侧卵巢切除术。术后1W开始用药，每两周用药1次，共6次。对照组腹腔内注射生理盐水1ml；化疗组腹腔内注射顺铂2mg／kg溶于1ml生理盐水中。术后13W处死各组动物，处死前用代谢笼收集24h空腹尿标本，自动生化分析仪测定尿钙浓度并计算出24h排泌量。氯胺T氧化法测尿羟脯氨酸(HOP)浓度并计算出24h排泌量；麻醉动物，开腹后下腔静脉取血离心，放免法测骨钙素(BGP)、血尿素氮(BUN)；取腰椎L4-6椎体，双能X线骨密度测量仪测腰椎骨密度。结果化疗组与对照组相比，骨密度降低，24h尿HOP及24h尿Ca定量升高，均有显著意义，血BGP无差异。结论本实验表明顺铂对大鼠的骨代谢存在直接的不良影响，使骨吸收增加，表现为松质骨骨密度降低。     

Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma

The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4±2.2 (±SD) years after chemotherapy (total cumulative dose: methotrexate 41±31 g/m², ifosfamide 39±14 g/m², cisplatin 674±188 mg/m²) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m² in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications. Received September 29, 1997; received in revised form December 12, 1997; accepted February 18, 1998     

晚期非小细胞肺癌内科治疗的探讨

目的 观察健择/顺铂、泰素/顺铂、泰索帝／顺铂、易瑞沙治疗晚期非小细胞肺癌的疗效、毒副反应及费用情况。方法 经病理学证实的99例晚期非小细胞肺癌患者分成四组。A组：健择1000mg／m^2d1.8.15＋顺铂100mg／m^2d1，4周为1个周期，连用4个周期；B组：泰素135mg／m^2d1＋顺铂75mg/m^2d2．3周为1个周期，连用4个周期；C组：泰索帝75mg/m^2d1＋顺铂75mg/m^2d1，3周为1个周期，连用4个周期；D组：易瑞沙250mg，每日1次，30d为1个周期，连用6个周期。结果 总有效率：A组为23．3％，B组21．4％，C组26．0％，D组23．5％；中位生存期：A组为8．1个月，B组7．8个月，C组8．0个月，D组7．6个月；毒副反应A、B、C三组骨髓抑制及消化道症状比较常见，但三组间无明显的差异性（P〉0．05），而D组这些毒副反应则明显减少；费用：D组最高，其次为C组，A、B两组相当。结论 选择A、B组比较适合于普通群众，而对于经济条件比较好的或者不能耐受化疗药物毒副反应的病人可选用易瑞沙。     

支气管动脉灌注化疗治疗非小细胞肺癌的组织学疗效(附63例分析)

目的评价非小细胞肺癌对支气管动脉灌注以顺铂为主的联合化疗药物的敏感性。材料与方法回顾性分析术前经支气管动脉灌注化疗的63例非小细胞肺癌的病理组织学疗效,分析组织学疗效与细胞类型和临床分期的关系。结果63例中Ⅲ级反应8例(鳞癌7例、腺癌1例),Ⅱ级反应10例(鳞癌9例、其它癌1例),Ⅰ级反应23例(鳞癌15例、腺癌7例、其它1例),0级反应22例(鳞癌11例、腺癌11例)。结论支气管动脉灌注以顺铂为主的联合化疗药物是有效治疗非小细胞肺癌的方案,其中对鳞癌比腺癌敏感,不同临床分期间的化疗敏感性无显著性差异。     

Dishevelled2在鼻咽癌顺铂耐药中的作用研究?

目的：探讨散乱蛋白2(Dishevelled2,DVL2)对鼻咽癌顺铂化疗敏感性的影响,为进一步研究 DVL2在肿瘤化疗耐药中的作用机制奠定前期基础。方法转染 pcDNA3.1-DVL2至鼻咽癌细胞5-8F,并用不同浓度(0,1,2,4,8,10,20μmol/L)的顺铂处理细胞,MTT 检测过转染 DVL2对5-8F 顺铂抑制率及半数抑制浓度(IC50)的影响,流式检测 DVL2高表达对顺铂的5-8F 细胞凋亡的影响,Western blotting 检测 DVL2对 Wnt/β-catenin 信号的影响。结果过表达 DVL2明显降低了顺铂对5-8F 的抑制率,提高了其 IC50,同时过表达 DVL2明显降低了顺铂诱导的5-8F 细胞的凋亡,进一步研究显示,过表达 DVL2明显增加了β-catenin 及其靶基因 P-gp 和 Survivin 的蛋白表达。结论过表达 DVL2可通过上调 Wnt/β-catenin 信号增强耐药相关蛋白 P-gp、Survivin 的表达,从而诱发鼻咽癌顺铂耐药。     

Transarterial Chemoembolization Using Cisplatin Powder in a Rabbit Model of Liver Cancer

The purpose of this study was to investigate the pharmacological advantages of transarterial chemoembolization (TACE) with cisplatin powder for hypervascular hepatic tumors in animal experiments. VX2 tumors were transplanted to the livers of nine rabbits. Cisplatin (1 mg/kg) was infused into the proper hepatic artery. In the cisplatin-HAI group, cisplatin solution was infused. In the cisplatin-GS-TACE group, after infusion of cisplatin solution, gelatin sponge particles were used for embolization. In the cisplatin-Lp-TACE group, after infusion of a cisplatin powder and lipiodol (10 mg/ml) suspension, gelatin sponge particles were used for embolization. Before and after administration, platinum concentrations in plasma were measured. Using liver specimens that were excised 60 min after infusion, platinum concentrations in tumorous and nontumorous liver tissues were measured. The mean platinum concentration in tumorous tissue was 0.88 μg/ml for the cisplatin-HAI group, 1.23 μg/ml for the cisplatin-GS-TACE group, and 12.65 μg/ml for the cisplatin-Lp-TACE group. The platinum concentration for the cisplatin-Lp-TACE group was significantly higher than that for the cisplatin-HAI group (p = 0.004) and the cisplatin-GS-TAE group (p = 0.004). The mean platinum concentration in nontumorous liver tissue was 0.98 μg/ml for the cisplatin-HAI group, 1.13 μg/ml for the cisplatin-GS-TACE group, and 1.09 μg/ml for the cisplatin-Lp-TACE group; no significant differences were seen. At both 5 and 10 min after infusion, the platinum concentrations for the cisplatin-Lp-TACE group were lower than those for the other two groups. The present results suggest that TACE using cisplatin powder/lipiodol suspension and gelatin sponge for hypervascular hepatic tumors has a number of pharmacological advantages. This material was presented at 2007 CIRSE.     

周剂量紫杉醇联合顺铂治疗晚期食管癌临床观察

目的观察周剂量紫杉醇（PTX）加顺铂（DDP）联合化疗治疗晚期食管癌的近期疗效和毒副反应。方法晚期食管癌患者48例分为两组，PTX＋DDP组：PTX80mg／m^2静滴第1，8天；顺铂20mg／d静滴第1～5天。5-Fu＋DDP＋CF组：5-Fu500mg／m^2静滴，第1～5天；DDP20mg／d静滴第1～5天，CF100mg／次静滴，在5-Fu前2h内给药第1～5天，21天为1周期，2周期后按UICC标准评价近期疗效和毒副反应。结果PTX＋DDP方案治疗20例食管癌患者有效率为70％；5-Fu＋DDP＋CF方案治疗28例的有效率为50％。前一联合方案总有效率高于后者，有显著性差异（P〈0．05），不良反应也较后者重，但大多数患者能耐受，主要为剂量限制性毒性，表现为Ⅱ～Ⅲ度为主的骨髓抑制。结论周剂量紫杉醇联合顺铂治疗晚期食管癌近期疗效显著，毒副反应小。     

艾迪联合长春瑞滨加顺铂方案治疗晚期非小细胞肺癌疗效观察

目的观察和评价艾迪注射液联合长春瑞滨加顺铂方案（NP方案）治疗晚期非小细胞肺癌的疗效和毒性。方法将我科近几年收治的52例晚期非小细胞肺癌患者随机分为联合治疗组和化疗组：联合治疗组采用艾迪注射液联合长春瑞滨加顺铂方案，化疗组采用长春瑞滨加顺铂方案（NP方案）。3周期化疗后进行疗效，毒性对比研究。结果联合治疗组和化疗组近期有效率分别为46％和42％，疾病进展时间（TTP）分别为6．8月和5.3月．中位生存时间分别为10．7月和9．4月，1年生存率分别为42％和38％。两组间比较差异均无显著性（P〉0．05）。联合治疗组在恶心、呕吐、骨髓抑制等毒性反应发生率方面低于化疗组，差异有显著性（P〈0．05）。结论艾迪注射液联合长春瑞滨加顺铂方案与NP方案相比．疗效相似，但毒性反应低于NP组，患者更易接受，可广泛用于临床。