胰腺癌肝转移脂质体阿霉素介入化疗实验研究
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摘要
胰腺癌在最初诊断时即有约50%的患者出现肝转移,另外行根治性切除术后的患者约70%最先出现转移的部位包括肝脏,而目前对肝转移瘤缺乏有效治疗方法,这是胰腺癌治疗中面临的最大困难之一。
当今临床医疗中对胰腺癌肝转移瘤最常采用的治疗方法是介入治疗,其所用药物借鉴胰腺癌全身化疗或肝癌介入化疗,包括吉西他滨、顺铂、5-Fu以及阿霉素等多种药物。但是所有这些药物都面临毒副作用大,患者耐受性差,用药剂量很难达到最佳治疗剂量,而且最重要的是有效率较低。胰腺癌由于缺乏大型动物细胞系,无法进行筛选最佳用药方案的介入化疗实验研究。脂质体阿霉素由于脂质体载药的原因改变了阿霉素的药代动力学特征及组织分布规律,提高疗效的同时降低了心脏及全身各系统的毒副作用。本课题采用裸鼠胰腺癌肝转移模型,首次通过脾脏注射给药模拟介入化疗来比较脂质体阿霉素与阿霉素相比用于胰腺癌肝转移介入化疗的优势,以筛选胰腺癌肝转移介入化疗新的药物剂型。
本课题采用薄层水化法和主动载药法制备PEG-DSPE(polyethylene glycol-distearoylphasphatidyle-thano-lamine)修饰的脂质体阿霉素,经检测所制备的脂质体阿霉素粒径在110±10nm范围内,阿霉素药物包封率为94.21%,长期放置后再次检测性质稳定,适合用于动物实验研究。
采用脾脏注射给药模拟介入化疗为本实验首次采用,其可行性原因有以下三点:(1)解剖学上脾脏内血液几乎全部首先回流肝脏,这点与肝动脉或门静脉给药类似。(2)染料法观察显示脾脏下极注射美兰溶液的同时肝脏左叶部分区域出现蓝染,继续给药蓝染区域扩散至全肝,说明肝左叶首先出现蓝染的区域为脾脏下极注射给药时药物首先到达的区域。(3)在门静脉高压模型的实验性治疗中有采用脾脏注射给药的报道。在采用脾脏注射给药模拟介入化疗和尾静脉注射给药模拟全身化疗的治疗实验中脾脏注射给药组疗效优于尾静脉给药组,进一步证实此给药途径虽不能替代肝动脉给药但可以模拟之。
采用上下增减剂量法(up and down procedure,UPD)测得脂质体阿霉素和阿霉素经脾脏给药对裸鼠的LD50分别为30.4mg/Kg和17.65mg/Kg,说明脂质体阿霉素可以降低药物的毒副作用,并提高药物的安全剂量。
通过药物组织分布实验发现脂质体阿霉素经脾脏注射给药与尾静脉注射给药相比降低了动物心脏、肺脏及肾脏内药物浓度,提高了肝脏及脾脏内药物浓度,同时血液内药物峰浓度降低,曲线下面积减小,从药代动力学角度解释了脾脏注射给药模拟介入化疗疗效更佳的原因。
由于本实验采用的模型每只动物需要进行两次手术,费时较长,一次实验所能进行的动物只数有限,药效学实验中以剂量为3mg/kg和6mg/kg阿霉素做对照组分别进行了实验,结果显示脂质体阿霉素1.5mg/kg,3mg/kg和6mg/kg三个剂量疗效均有显著差异,呈剂量依赖性。3mg/kg脂质体阿霉素与相同剂量阿霉素相比肿瘤缩小更明显(P＜0.05),与相同剂量吉西他滨加顺铂无统计学差异(P＞0.05),脂质体阿霉素6mg/kg和9mg/kg疗效均较好,无显著差异。6mg/kg脂质体阿霉素与相同剂量阿霉素相比疗效无显著性差异,与相同剂量吉西他滨加顺铂相比肿瘤显著缩小(P＜0.05)。脂质体阿霉素各剂量组均未出现明显毒性反应,阿霉素组(6mg/kg)和吉西他滨加顺铂组(6mg/kg)出现明显毒性反应,均有约半数动物死亡。药效学实验进一步说明脂质体阿霉素用于介入化疗与阿霉素相比疗效显著提高,毒性显著降低,且6mg/kg脂质体阿霉素为最佳实验治疗剂量。
上述实验资料表明,本实验所制备的PEG-DSPE修饰的脂质体阿霉素理化性质均一、稳定,应用于介入化疗能够取得较阿霉素更好的疗效,同时降低了阿霉素的毒副作用,有望成为新的介入化疗药物剂型。
Nearly 50%of pancreatic cancer patients suffer liver metastasis at the time of diagnosis,and the first site of recurrence for more than 70%of radically resected patients includes liver,what makes thing worse is till now there are no effective treatmet for liver metastasis of pancreatic cancer.This is one of the largest difficulties we have to faced with in the treatment of pancreatic cancer.
Now the mostly used method for liver metastasis of pancreatic cancer is interventional therapy,and the adopted drugs include gemcitabine,cisplatin, 5-fluorouracil and doxorubicin according to the systemic chemotherapy of pancreatic cancer or interventional chemotheary of primary liver cancer.However all these drugs used now have great toxic side effect,bad tolerance so it's hard to reach optimal therapeutic dosage,and what's more the response rate is low.As we know for pancreatic cancer there is no cell line for big animal transplantation,so the experimental study for screening optimal interventional chemotherapy drug schedule is hard to perform.For the reason of liposome,liposomal doxorubicin has different pharmacokinetics characteristic and tissue distribution pattern with doxorubicin,then the therapeutic effect was improved and the toxic side effect of heart and other system was decreased.The nude mouse pancreatic cancer liver metastasis model was adopted in this study,and for the first time injection through spleen imitating interventional chemotherapy was introduced in animal experiments to compare the therapeutic effect and toxic side effect of liposomal doxorubicin and doxorubicin,eventually find a new drug for the interventional therapy of liver metastasis of pancreatic cancer.
PEG-DSPE(polyethylene glycol-distearoylphasphatidyle-thano-lamine) modified liposomal doxorubicin was prepared by lamellar hydration and initiative loading methods in our laboratory in this study.The diameter of the prepared liposomal doxorubicin was tested in the range of 110±10nm,and the entrapment rate was 94.21%.Lay up it for 3months and test again,we found it's stable,so it's suitable for animal experiment.
It's the first time that injection through spleen was adopted to imitate interventional chemotherapy,the feasibility can be explained from the 3 points mentioned below:(1)As to anatomy,the blood in spleen refluxs almost totally to liver, this is similar to injection through hepatic artery or portal vein.(2) When dyes was injected into spleen,you can see the left part of liver turned blue at the same time,and as injection going on,whole liver turned blue,this phenomenon told us this channel of administration is nearly unhindered.(3) As reported in the portal hypertension models, injection through spleen is an administration route.In the therapeutic experiments the group of injection through spleen showed better outcome than the group of injection through caudal vein,so it's further confirmed that this administration route could imitate interventional chemotherapy.
The LD_(50) of liposomal doxorubicin and doxorubicin were 30.4mg/Kg and 17.65mg/Kg respectively examined by up and down procedure,so liposomal doxorubicin had lower toxic side effect and higher safty dose.
In the tissue distribution experiment we found that the drug concentrations in heart,lung and kidney were lower when administrated through spleen injection compared to caudal vein,while the drug concentrations in liver and spleen were higher.In blood the peak concentration was lower and area under the curve was smaller for spleen injection group compared to caudal vein injection group.These results explained why the therapeutic effect for interventional chemotherapy was better from the point view of pharmacokinetics.
For the model adopted in this study was time-consuming,the animal we can perform in one time of experiment was limited.So we complished 2 experiments about therapeutic effect of the drug accoding to the different dose of doxorubicin (3mg/kg and 6mg/kg) in control group.The results showed in the doses of 1.5mg/kg, 3mg/kg and 6mg/kg liposomal doxorubicin produced significantly different effect, that mean the effect was in a manner of dose dependent.In the doses of 6mg/kg and 9mg/kg the effect of liposomal doxorubicin turned to be same perfect,and there was no difference between them(P＞0.05).In the dose level of 3mg/kg liposomal doxorubicin had a better effect than doxorubicin(P＜0.05),while it's no better than gemcitabine combined with cisplatin(P＞0.05).In the dose level of 6mg/kg liposomal doxorubicin and doxorubicin had no significantly different effect,but it's much better than gemcitabine combined with cisplatin(P＜0.05).There was no obvious toxic side effect in all the four doses of liposomal doxorubicin,while doxorubicin(6mg/kg) and gemcitabine combined with cisplatin(6mg/kg) led about half of the animal dead in each group.The results of this part further confirmed liposomal doxorubicin had a significantly better effect and lower toxic side effect than doxorubicin,and 6mg/kg was the optimal dose in animal experiments.
The results of above experiments showed the PEG-DSPE modified liposomal doxorubicin prepared in this laboratory was uniform and stable,when applied in interventional chemotherapy it could get a better therapeutic effect and lower toxic side effect than doxorubicin,so it's a potential new pharmaceutical dosage form in interventional chemotherapy.
当今临床医疗中对胰腺癌肝转移瘤最常采用的治疗方法是介入治疗,其所用药物借鉴胰腺癌全身化疗或肝癌介入化疗,包括吉西他滨、顺铂、5-Fu以及阿霉素等多种药物。但是所有这些药物都面临毒副作用大,患者耐受性差,用药剂量很难达到最佳治疗剂量,而且最重要的是有效率较低。胰腺癌由于缺乏大型动物细胞系,无法进行筛选最佳用药方案的介入化疗实验研究。脂质体阿霉素由于脂质体载药的原因改变了阿霉素的药代动力学特征及组织分布规律,提高疗效的同时降低了心脏及全身各系统的毒副作用。本课题采用裸鼠胰腺癌肝转移模型,首次通过脾脏注射给药模拟介入化疗来比较脂质体阿霉素与阿霉素相比用于胰腺癌肝转移介入化疗的优势,以筛选胰腺癌肝转移介入化疗新的药物剂型。
本课题采用薄层水化法和主动载药法制备PEG-DSPE(polyethylene glycol-distearoylphasphatidyle-thano-lamine)修饰的脂质体阿霉素,经检测所制备的脂质体阿霉素粒径在110±10nm范围内,阿霉素药物包封率为94.21%,长期放置后再次检测性质稳定,适合用于动物实验研究。
采用脾脏注射给药模拟介入化疗为本实验首次采用,其可行性原因有以下三点:(1)解剖学上脾脏内血液几乎全部首先回流肝脏,这点与肝动脉或门静脉给药类似。(2)染料法观察显示脾脏下极注射美兰溶液的同时肝脏左叶部分区域出现蓝染,继续给药蓝染区域扩散至全肝,说明肝左叶首先出现蓝染的区域为脾脏下极注射给药时药物首先到达的区域。(3)在门静脉高压模型的实验性治疗中有采用脾脏注射给药的报道。在采用脾脏注射给药模拟介入化疗和尾静脉注射给药模拟全身化疗的治疗实验中脾脏注射给药组疗效优于尾静脉给药组,进一步证实此给药途径虽不能替代肝动脉给药但可以模拟之。
采用上下增减剂量法(up and down procedure,UPD)测得脂质体阿霉素和阿霉素经脾脏给药对裸鼠的LD50分别为30.4mg/Kg和17.65mg/Kg,说明脂质体阿霉素可以降低药物的毒副作用,并提高药物的安全剂量。
通过药物组织分布实验发现脂质体阿霉素经脾脏注射给药与尾静脉注射给药相比降低了动物心脏、肺脏及肾脏内药物浓度,提高了肝脏及脾脏内药物浓度,同时血液内药物峰浓度降低,曲线下面积减小,从药代动力学角度解释了脾脏注射给药模拟介入化疗疗效更佳的原因。
由于本实验采用的模型每只动物需要进行两次手术,费时较长,一次实验所能进行的动物只数有限,药效学实验中以剂量为3mg/kg和6mg/kg阿霉素做对照组分别进行了实验,结果显示脂质体阿霉素1.5mg/kg,3mg/kg和6mg/kg三个剂量疗效均有显著差异,呈剂量依赖性。3mg/kg脂质体阿霉素与相同剂量阿霉素相比肿瘤缩小更明显(P＜0.05),与相同剂量吉西他滨加顺铂无统计学差异(P＞0.05),脂质体阿霉素6mg/kg和9mg/kg疗效均较好,无显著差异。6mg/kg脂质体阿霉素与相同剂量阿霉素相比疗效无显著性差异,与相同剂量吉西他滨加顺铂相比肿瘤显著缩小(P＜0.05)。脂质体阿霉素各剂量组均未出现明显毒性反应,阿霉素组(6mg/kg)和吉西他滨加顺铂组(6mg/kg)出现明显毒性反应,均有约半数动物死亡。药效学实验进一步说明脂质体阿霉素用于介入化疗与阿霉素相比疗效显著提高,毒性显著降低,且6mg/kg脂质体阿霉素为最佳实验治疗剂量。
上述实验资料表明,本实验所制备的PEG-DSPE修饰的脂质体阿霉素理化性质均一、稳定,应用于介入化疗能够取得较阿霉素更好的疗效,同时降低了阿霉素的毒副作用,有望成为新的介入化疗药物剂型。
Nearly 50%of pancreatic cancer patients suffer liver metastasis at the time of diagnosis,and the first site of recurrence for more than 70%of radically resected patients includes liver,what makes thing worse is till now there are no effective treatmet for liver metastasis of pancreatic cancer.This is one of the largest difficulties we have to faced with in the treatment of pancreatic cancer.
Now the mostly used method for liver metastasis of pancreatic cancer is interventional therapy,and the adopted drugs include gemcitabine,cisplatin, 5-fluorouracil and doxorubicin according to the systemic chemotherapy of pancreatic cancer or interventional chemotheary of primary liver cancer.However all these drugs used now have great toxic side effect,bad tolerance so it's hard to reach optimal therapeutic dosage,and what's more the response rate is low.As we know for pancreatic cancer there is no cell line for big animal transplantation,so the experimental study for screening optimal interventional chemotherapy drug schedule is hard to perform.For the reason of liposome,liposomal doxorubicin has different pharmacokinetics characteristic and tissue distribution pattern with doxorubicin,then the therapeutic effect was improved and the toxic side effect of heart and other system was decreased.The nude mouse pancreatic cancer liver metastasis model was adopted in this study,and for the first time injection through spleen imitating interventional chemotherapy was introduced in animal experiments to compare the therapeutic effect and toxic side effect of liposomal doxorubicin and doxorubicin,eventually find a new drug for the interventional therapy of liver metastasis of pancreatic cancer.
PEG-DSPE(polyethylene glycol-distearoylphasphatidyle-thano-lamine) modified liposomal doxorubicin was prepared by lamellar hydration and initiative loading methods in our laboratory in this study.The diameter of the prepared liposomal doxorubicin was tested in the range of 110±10nm,and the entrapment rate was 94.21%.Lay up it for 3months and test again,we found it's stable,so it's suitable for animal experiment.
It's the first time that injection through spleen was adopted to imitate interventional chemotherapy,the feasibility can be explained from the 3 points mentioned below:(1)As to anatomy,the blood in spleen refluxs almost totally to liver, this is similar to injection through hepatic artery or portal vein.(2) When dyes was injected into spleen,you can see the left part of liver turned blue at the same time,and as injection going on,whole liver turned blue,this phenomenon told us this channel of administration is nearly unhindered.(3) As reported in the portal hypertension models, injection through spleen is an administration route.In the therapeutic experiments the group of injection through spleen showed better outcome than the group of injection through caudal vein,so it's further confirmed that this administration route could imitate interventional chemotherapy.
The LD_(50) of liposomal doxorubicin and doxorubicin were 30.4mg/Kg and 17.65mg/Kg respectively examined by up and down procedure,so liposomal doxorubicin had lower toxic side effect and higher safty dose.
In the tissue distribution experiment we found that the drug concentrations in heart,lung and kidney were lower when administrated through spleen injection compared to caudal vein,while the drug concentrations in liver and spleen were higher.In blood the peak concentration was lower and area under the curve was smaller for spleen injection group compared to caudal vein injection group.These results explained why the therapeutic effect for interventional chemotherapy was better from the point view of pharmacokinetics.
For the model adopted in this study was time-consuming,the animal we can perform in one time of experiment was limited.So we complished 2 experiments about therapeutic effect of the drug accoding to the different dose of doxorubicin (3mg/kg and 6mg/kg) in control group.The results showed in the doses of 1.5mg/kg, 3mg/kg and 6mg/kg liposomal doxorubicin produced significantly different effect, that mean the effect was in a manner of dose dependent.In the doses of 6mg/kg and 9mg/kg the effect of liposomal doxorubicin turned to be same perfect,and there was no difference between them(P＞0.05).In the dose level of 3mg/kg liposomal doxorubicin had a better effect than doxorubicin(P＜0.05),while it's no better than gemcitabine combined with cisplatin(P＞0.05).In the dose level of 6mg/kg liposomal doxorubicin and doxorubicin had no significantly different effect,but it's much better than gemcitabine combined with cisplatin(P＜0.05).There was no obvious toxic side effect in all the four doses of liposomal doxorubicin,while doxorubicin(6mg/kg) and gemcitabine combined with cisplatin(6mg/kg) led about half of the animal dead in each group.The results of this part further confirmed liposomal doxorubicin had a significantly better effect and lower toxic side effect than doxorubicin,and 6mg/kg was the optimal dose in animal experiments.
The results of above experiments showed the PEG-DSPE modified liposomal doxorubicin prepared in this laboratory was uniform and stable,when applied in interventional chemotherapy it could get a better therapeutic effect and lower toxic side effect than doxorubicin,so it's a potential new pharmaceutical dosage form in interventional chemotherapy.
引文
Anderson KE,Mack TM,Silverman DT (2006).Cancer of the pancreas.In:Schottenfeld D,Fraumeni Jr JF,eds.,Cancer Epidemiology and Prevention.New York:Oxford University Press.721-762.
Bayoumi TA,Torchilin VP(2009).Tumor-targeted nanomedicines:enhanced antitumor efficacy in vivo of doxorubicin-loaded,long-circulating liposomes modified with cancer-specific monoclonal antibody.Clin Cancer Res.15:1973-80.Epub 2009 Mar 10.
Boyle P,Smans M (2008).I ARC Scientiic Publications Number 156,Atlas of cancer mortality in the European Union and the European Economic Area 1993-1997.Lyon,France International Agency for Research on Cancer.
Cantore M,Pederzoli P,Cornalba G,Fiorentini G,Guadagni S,Miserocchi L,Frassoldati A,Ceravolo C,Smerieri F,Muchmore JH(2000).Intra-arterial chemotherapy for unresectable pancreatic cancer.Ann Oncol.11:569-73.
Fuchs CS,Colditz GA,Stampfer MJ,et al.(1996).A pro-spective study of cigarette smoking and the risk of pancreatic cancer.Arch Intern Med.156:2255-2260.
Jemal A,Siegel R,Ward E,et al.(2008).Cancer Statistics,CA Cancer J Clin.58:71-96.
Mambrini A,Sanguinetti F,Pacetti P,Caudana R,lacono C,Guglielmi A,Guadagni S,Del Freo A,Fiorentini G,Cantore M(2006).Intra-arterial infusion of 5-fluorouracil,leucovorin,epirubicin and carboplatin (FLEC regimen)in unresectable pancreatic cancer:results of a ten-year experience.In Vivo.20:751-5.
Sasada T,Denno R,Tanaka T,Kanai M,Mizukami Y,Kohno S,Takabayashi A(2008).Intra-arterial infusion chemotherapy with 5-fluorouracil and cisplatin in advanced pancreatic cancer:a feasibility study.Am J Clin Oncol.31:71-8.
Sperti C,Pasquali C,Piccoli A,Pedrazzoli S(1997).Recurrence after resection for ductal adenocarcinoma of the pancreas.World J.Surg.21:195-200.
傅德良,倪泉兴,虞先浚,张群华,华宇明,张延龄,王莉(2002).胰腺区域性动脉灌注治疗胰腺癌的实验研究.中华医学杂志.82:371-375.
张弘炜,范健(2000).脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学.28:362-364.
Haran G,Cohen R,Bar LK,Barenholz Y(1993).Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases.Biochim BiophysActa.1151:201-15.
Papahadjopoulos D,Allen TM,Gabizon A,Mayhew E,Matthay K,Huang SK,Lee KD,Woodle MC,Lasic DD,Redemann C(1991).Sterically stabilized liposomes:improvements in pharmacokinetics and antitumor therapeutic efficacy.Proc Natl Acad Sci US A.88:11460-4.
Parr MJ,Ansell SM,Choi LS,Cullis PR(1994).Factors influencing the retention and chemical stability of polyethylene glycol-lipid conjugates incorporated into large unilamellar vesicles.Biochim BiophysActa.1195:21-30.
Suzuki Y,Wakita D,Chamoto K,Narita Y,Tsuji T,Takeshima T,Gyobu H,Kawarada Y,Kondo S,Akira S,Katoh H,Ikeda H,Nishimura T(2004).Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity.Cancer Res.64:8754-60.
梁力建,吕明德,黄洁夫(1998).裸小鼠人肝癌移植模型的抗雄激素治疗.中华医学杂志.78:299-300.
刘德纯,党诚学,白纪纲,陈武科,王作仁(2004).硫酸昆布多糖在仓鼠胰腺癌肝转移模型中抑制作用的研究.中华肝胆外科杂志.10:831-4.
郜永顺,陈孝平,李开艳,丁磊,吴在德(2006).人肝癌组织裸鼠原位种植模型体内筛选化疗药物可行性研究.肿瘤基础与临床.19:282-4.
吴汉平,梁惠民郑传胜,冯敢生(2002).不同途径门脉靶向给药治疗鼠肝硬化门脉高压的可行性研究.介入放射学杂志.11:114-6.
OECD(2001).Guideline for the Testing of Chemicals.Acute Oral Toxicity:Up and Down Prodedure.425.Adopted:17th,1211.
张林媛,孙金秀(2003).上下增减剂量法和Horn's测定LD_(50)的研究.卫生毒理学杂志.17:2342-61.
张弘炜,范健(2000).脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学.28:362-4.
范健,文旭,缪玉山,翁帼英(2001).脂质体阿霉素与游离阿霉素在大鼠体内药代动力学.中国药科大学学报.32:354-8.
王心如(2003).毒理学基础[M].北京:人民卫生出版社.1032-41
Hu T,Le Q,Wu Z,Wu W(2007).Determination of doxorubicin in rabbit ocular tissues and pharmacokinetics after intravitreal injection of a single dose of doxorubicin-loaded poly-beta-hydroxybutyrate microspheres.J Pharm Biomed Anal.43:263-9.Epub 2006 Aug 1.
Liu Y,Yang Y,Liu X,Jiang T(2008).Quantification of pegylated liposomal doxorubicin and doxorubicinol in rat plasma by liquid chromatography/electrospray tandem mass spectroscopy:Application to preclinical pharmacokinetic studies.Talanta.74:887-95.Epub 2007 Jul 31.
Urva SR,Shin BS,Yang VC,Balthasar JP(2009).Sensitive high performance liquid chromatographic assay for assessment of doxorubicin pharmacokinetics in mouse plasma and tissues.J Chromatogr B Analyt Technol Biomed Life Sci.877:837-41.Epub 2009 Feb 11
Wei G,Xiao S,Si D,Liu C(2008).Improved HPLC method for doxorubicin quantification in rat plasma to study the pharmacokinetics of micelle-encapsulated and liposome-encapsulated doxorubicin formulations.Biomed Chromatogr.22:1252-8.
唐利安,陈知航,侯禹男,单成启,刘萍,程远国,王忠伟(2006).隐形盐酸阿霉素脂质体注射液药代动力学的实验研究.中国临床药理学杂志.22:292-4.
吴道澄,朴相浩,王执民,张国民,徐山淡,文爱东(1997).阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究.现代应用药学.14:24-7.
翟瑞仁,江森,赵炎,邹立家(1996).阿霉素脂质体腹腔内注射的药动学动物实验研究齐鲁肿瘤杂志.3:172-174.
Akaishi S,Kobari M,Takeda K,et al.Targeting chemotherapy using antibody-combined liposome against human pancreatic cancer cell-line.Tohoku J Exp Med.1995,175(1):29-42.
Fidler IJ,Fogler WE.Activation of tumoricidal properties in macrophages by lymphokines encapsulated in liposomes.Lymphokine Res.1982;1(3):73-77.
Hofheinz RD,Wilier A,Weisser A,et al.Pegylated liposomal doxorubicin in combination with mitomycin C,infusional 5-fluorouracil and sodium folinic acid.A phase-I-study in patients with upper gastrointestinal cancer.Br J Cancer,200417;90(10):1893-1897.
Kalra AV,Campbell RB.Development of 5-FU and doxorubicin-loaded cationic liposomes against human pancreatic cancer:Implications for tumor vascular targeting.Pharm Res.2006,23(12):2809-2817.
Ries LAG,Harkins D,Krapcho M,et al.,eds.SEERCancer Statistics Review,1975-2003[based on the November 2005 SEER data submission,posted to the SEER website 2006].Bethesda,Md:National Cancer Institute;2006.Available at:http://seer.cancer.gov/csr/1975_2003/Accessed September 24,2007.
Sasada T,Denno R,Tanaka T,et al.Intra-arterial infusion chemotherapy with 5-fluorouracil and cisplatin in advanced pancreatic cancer:a feasibility study.Am J Clin Oncol.2008,31(1):71-78.
Vaage J,Barber(?)-Guillem E,Abra R,et al.Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts.Cancer,1994,73(5):1478-1484.
Vaage J,Donovan D,Uster P,et al.Tumor uptake of doxorubicin in polyethylene glycol-coated liposomes and therapeutic effect against a xenografted human pancreatic carcinoma.Br J Cancer.1997;75(4):482-486.
陈卫东,张弘炜,范健.脂质体阿霉素对小鼠移植性肿瘤的治疗作用.现代医学,2002,30(6):358-360.
郜永顺,陈孝平,李开艳,丁磊,吴在德.人肝癌组织裸鼠原位种植模型体内筛选化疗药物可行性研究.肿瘤基础与临床.2006,19(4):282-284.
张弘炜,范健.脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学,2000,28(6):362-364.
周平红,秦新裕.脂质体阿霉素及其靶向治疗研究进展.中国临床医学,2002,9(4):331-334.
周平红,姚礼庆,秦新裕,等.磁性阿霉素脂质体靶向治疗裸鼠大肠癌的实验研究.中华医学杂志,2003,83(23):2073-2076.
Allendorf JD,Lauerman M,Bill A,et al.Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma:feasibility,efficacy,and survival.J Gastrointest Surg.2008;12(1):91-100.
Ammori JB,Colletti LM,Zalupski MM,et al.Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas.J Gastrointest Surg 2003;7:766-72.
Bakkevold K,Arnesjo B,Dahl O,Kambestad B.Adjuvant combination chemotherapy (AMF)following radical resection of carcinoma of the pancreas and papilla of vater-results of a controlled,prospective,randomised multicentre study.Eur J Can 1993;29A:698-703.
Burris 3rd HA,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial.J Clin Oncol 1997;6:2403-13.
Cleary SP,Gryfe R,Guindi M,et al.Prognostic factors in resected pancreatic adenocarcinoma:analysis of actual 5-year survivors.J Am Coll Surg 2004;198:722-31.
Cress RD,Yin DX,Clarke L,Bold R,Holly EA.Survival among patients with adenocarcinoma of the pancreas:a population-based study(United States).Cancer Causes Control 2006;17:403-9.
Douglass H.Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer.Cancer 1987;59:2006-10.
Greer SE,Pipas JM,Sutton JE,et al.Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma.J Am Coll Surg.2008;206(3):451-7.
Hoffman JP,Lipsitz S,Pisansky T,Weese JL,Solin L,Benson Ⅲ AB.Phase Ⅱ Trial of Preoperative radiation therapy and chemotherapy for patients with localized,resectable adenocarcinoma of the pancreas:an Eastern Cooperative Oncology Group Study.J Clin Oncol 1998;16:317-23.
Ishikawa O,Ohigashi H,Imaoka S,et al.Is the long-term survival rate improved by preoperative irradiation prior to Whipple's procedure for adenocarcinoma of the pancreatic head? Arch Surg 1994;129:1075-80.
Jemal A,Siegel R,Ward E,Murray T,Xu J,Thun MJ.Cancer statistics,2007.CA Cancer J Clin 2007;57:43-66.
Kaiser M,Ellenberg S.Pancreatic cancenadjuvant combined radiation and chemotherapy following curative resection.Arch Surg 1985;120:899-903.
Kim HJ,Czischke K,Brennan MF,et al.Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? J Gastrointest Surg 2002;6(5):763-9.
Klinkenbijl J,Jeekel J,Sahmoud T,et al.Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region.Phase Ⅲ trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group.Ann Surg 1999;230:776-84.
Kosuge T,Kiuchi T,Mukai K,Kakizoe T.A multicenter randomised controlled trial to evaluate the effect of adjuvant cisplatin and 5-Fluorouracil therapy after curative resection in cases of pancreatic cancer.Jpn J Clin Oncol 2006;36:159-65.
Moutardier V,Magnin V,Turrini O,et al.Assessment of pathologic response after preoperative chemotherapy and surgery in pancreatic adenocarcinoma.Int J Radiat Oncol Biol Phys 2004;60:437-43.
Neoptolemos J,Dunn J,Stocken D,et al.Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer:a randomised controlled trial.Lancet 2001;358:1576-85.
Neoptolemos J,Stocken D,Freiss H,et al.A randomised trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med 2004;350:1200-10.
Oettle H,Post S,Neuhaus P,et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer:a randomized controlled trial.JAMA 2007;297:267-77.
Pisters PWT,Wolff RA,Crane CH,Evans DB.Combined modality treatment for operable pancreatic adenocarcinoma.Oncology 2005;19(3).Pisters PWT,Abbruzzese JL,Janjan NA,et al.Rapid-fractionation preoperative chemoradiation,pancreaticodudenectomy,and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.J Clin Oncol 1998;16:3843-50.
Regine WF,Winter KW,Abrams R,et al.RTOG 9704 a phase Ⅲ study of adjuvant pre and post chemoradiation 5FU vs.gemcitabine for resected pancreatic adenocarcinoma.J Clin Oncol 2005;24(18S).[abstract 4007].
Stessin AM,Meyer JE,Sherr DL.Neoadjuvant Radiation is Associated with Improved Survival in Patients with Resectable Pancreatic Cancer:An Analysis of Data from the Surveillance,Epidemiology,and End Results (SEER)Registry.Int J Radiat Oncol Biol Phys.2008 Jun 4.
Safran H,Dipetrillo T,Iannitti D,et al.Gemcitabine,paclitaxel and radiation for locally advanced pancreatic cancer:a phase I trial.Int J Radiat Oncol Biol Phys 2002;54:137-41.
Safran H,Moore T,Iannitti D,et al.Paclitaxel and concurrent radiation for locally advanced pancreatic cancer.Int J Radiat Oncol Biol Phys 2001;49:1275-9.
Stocken D,Buchler M,Dervenis C,et al.Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer.Br J Cancer 2005;92:1372-81.
Sperti C,Pasquali C,PiccoliA,Pedrazzoli S.Recurrence after resection for ductal adenocarcinoma of the pancreas.World J Surg 1997;21:195-200.
Takada T,Amano H,Yasuda H,et al.Is postoperative adjuvant chemotherapy useful for gall bladder carcinoma? A phase Ⅲ multicentre prospective randomised controlled trial in patients with resected pancreaticobiliary carcinoma.Cancer 2002;95:1685-95.
Varadhachary GR,Tamm EP,Abbruzzese JL,et al.Borderline resectable pancreatic cancer:definitions,management and role of preoperative therapy.Ann Surg Oncol 2006;13:1035-46.
Vento P,Mustonen H,Joensuu T,et al.Impact of preoperative chemoradiotherapy on survival in patients with resectable pancreatic cancer.World J Gastroenterol.2007;13(21):2945-51.
White RR,Hurwitz HI,Morse MA,et al.Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.Ann Surg Oncol 2001;8:758-65.
Wolff RA,Evans DB,Crane CH,etal.Initial results of a preoperative gemcitabine-based chemoradiation for respectable pancreatic adenocarcinoma.Proc Am Soc Clin Oncol 2002;21:130a(abstract516).
Yeo CJ,Cameron JL,Lillemoe KD,et al.Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma.Part 2.Randomized controlled trial evaluating survival,morbidity and mortality.Ann Surg 2002;236:355-66.
Bayoumi TA,Torchilin VP(2009).Tumor-targeted nanomedicines:enhanced antitumor efficacy in vivo of doxorubicin-loaded,long-circulating liposomes modified with cancer-specific monoclonal antibody.Clin Cancer Res.15:1973-80.Epub 2009 Mar 10.
Boyle P,Smans M (2008).I ARC Scientiic Publications Number 156,Atlas of cancer mortality in the European Union and the European Economic Area 1993-1997.Lyon,France International Agency for Research on Cancer.
Cantore M,Pederzoli P,Cornalba G,Fiorentini G,Guadagni S,Miserocchi L,Frassoldati A,Ceravolo C,Smerieri F,Muchmore JH(2000).Intra-arterial chemotherapy for unresectable pancreatic cancer.Ann Oncol.11:569-73.
Fuchs CS,Colditz GA,Stampfer MJ,et al.(1996).A pro-spective study of cigarette smoking and the risk of pancreatic cancer.Arch Intern Med.156:2255-2260.
Jemal A,Siegel R,Ward E,et al.(2008).Cancer Statistics,CA Cancer J Clin.58:71-96.
Mambrini A,Sanguinetti F,Pacetti P,Caudana R,lacono C,Guglielmi A,Guadagni S,Del Freo A,Fiorentini G,Cantore M(2006).Intra-arterial infusion of 5-fluorouracil,leucovorin,epirubicin and carboplatin (FLEC regimen)in unresectable pancreatic cancer:results of a ten-year experience.In Vivo.20:751-5.
Sasada T,Denno R,Tanaka T,Kanai M,Mizukami Y,Kohno S,Takabayashi A(2008).Intra-arterial infusion chemotherapy with 5-fluorouracil and cisplatin in advanced pancreatic cancer:a feasibility study.Am J Clin Oncol.31:71-8.
Sperti C,Pasquali C,Piccoli A,Pedrazzoli S(1997).Recurrence after resection for ductal adenocarcinoma of the pancreas.World J.Surg.21:195-200.
傅德良,倪泉兴,虞先浚,张群华,华宇明,张延龄,王莉(2002).胰腺区域性动脉灌注治疗胰腺癌的实验研究.中华医学杂志.82:371-375.
张弘炜,范健(2000).脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学.28:362-364.
Haran G,Cohen R,Bar LK,Barenholz Y(1993).Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases.Biochim BiophysActa.1151:201-15.
Papahadjopoulos D,Allen TM,Gabizon A,Mayhew E,Matthay K,Huang SK,Lee KD,Woodle MC,Lasic DD,Redemann C(1991).Sterically stabilized liposomes:improvements in pharmacokinetics and antitumor therapeutic efficacy.Proc Natl Acad Sci US A.88:11460-4.
Parr MJ,Ansell SM,Choi LS,Cullis PR(1994).Factors influencing the retention and chemical stability of polyethylene glycol-lipid conjugates incorporated into large unilamellar vesicles.Biochim BiophysActa.1195:21-30.
Suzuki Y,Wakita D,Chamoto K,Narita Y,Tsuji T,Takeshima T,Gyobu H,Kawarada Y,Kondo S,Akira S,Katoh H,Ikeda H,Nishimura T(2004).Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity.Cancer Res.64:8754-60.
梁力建,吕明德,黄洁夫(1998).裸小鼠人肝癌移植模型的抗雄激素治疗.中华医学杂志.78:299-300.
刘德纯,党诚学,白纪纲,陈武科,王作仁(2004).硫酸昆布多糖在仓鼠胰腺癌肝转移模型中抑制作用的研究.中华肝胆外科杂志.10:831-4.
郜永顺,陈孝平,李开艳,丁磊,吴在德(2006).人肝癌组织裸鼠原位种植模型体内筛选化疗药物可行性研究.肿瘤基础与临床.19:282-4.
吴汉平,梁惠民郑传胜,冯敢生(2002).不同途径门脉靶向给药治疗鼠肝硬化门脉高压的可行性研究.介入放射学杂志.11:114-6.
OECD(2001).Guideline for the Testing of Chemicals.Acute Oral Toxicity:Up and Down Prodedure.425.Adopted:17th,1211.
张林媛,孙金秀(2003).上下增减剂量法和Horn's测定LD_(50)的研究.卫生毒理学杂志.17:2342-61.
张弘炜,范健(2000).脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学.28:362-4.
范健,文旭,缪玉山,翁帼英(2001).脂质体阿霉素与游离阿霉素在大鼠体内药代动力学.中国药科大学学报.32:354-8.
王心如(2003).毒理学基础[M].北京:人民卫生出版社.1032-41
Hu T,Le Q,Wu Z,Wu W(2007).Determination of doxorubicin in rabbit ocular tissues and pharmacokinetics after intravitreal injection of a single dose of doxorubicin-loaded poly-beta-hydroxybutyrate microspheres.J Pharm Biomed Anal.43:263-9.Epub 2006 Aug 1.
Liu Y,Yang Y,Liu X,Jiang T(2008).Quantification of pegylated liposomal doxorubicin and doxorubicinol in rat plasma by liquid chromatography/electrospray tandem mass spectroscopy:Application to preclinical pharmacokinetic studies.Talanta.74:887-95.Epub 2007 Jul 31.
Urva SR,Shin BS,Yang VC,Balthasar JP(2009).Sensitive high performance liquid chromatographic assay for assessment of doxorubicin pharmacokinetics in mouse plasma and tissues.J Chromatogr B Analyt Technol Biomed Life Sci.877:837-41.Epub 2009 Feb 11
Wei G,Xiao S,Si D,Liu C(2008).Improved HPLC method for doxorubicin quantification in rat plasma to study the pharmacokinetics of micelle-encapsulated and liposome-encapsulated doxorubicin formulations.Biomed Chromatogr.22:1252-8.
唐利安,陈知航,侯禹男,单成启,刘萍,程远国,王忠伟(2006).隐形盐酸阿霉素脂质体注射液药代动力学的实验研究.中国临床药理学杂志.22:292-4.
吴道澄,朴相浩,王执民,张国民,徐山淡,文爱东(1997).阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究.现代应用药学.14:24-7.
翟瑞仁,江森,赵炎,邹立家(1996).阿霉素脂质体腹腔内注射的药动学动物实验研究齐鲁肿瘤杂志.3:172-174.
Akaishi S,Kobari M,Takeda K,et al.Targeting chemotherapy using antibody-combined liposome against human pancreatic cancer cell-line.Tohoku J Exp Med.1995,175(1):29-42.
Fidler IJ,Fogler WE.Activation of tumoricidal properties in macrophages by lymphokines encapsulated in liposomes.Lymphokine Res.1982;1(3):73-77.
Hofheinz RD,Wilier A,Weisser A,et al.Pegylated liposomal doxorubicin in combination with mitomycin C,infusional 5-fluorouracil and sodium folinic acid.A phase-I-study in patients with upper gastrointestinal cancer.Br J Cancer,200417;90(10):1893-1897.
Kalra AV,Campbell RB.Development of 5-FU and doxorubicin-loaded cationic liposomes against human pancreatic cancer:Implications for tumor vascular targeting.Pharm Res.2006,23(12):2809-2817.
Ries LAG,Harkins D,Krapcho M,et al.,eds.SEERCancer Statistics Review,1975-2003[based on the November 2005 SEER data submission,posted to the SEER website 2006].Bethesda,Md:National Cancer Institute;2006.Available at:http://seer.cancer.gov/csr/1975_2003/Accessed September 24,2007.
Sasada T,Denno R,Tanaka T,et al.Intra-arterial infusion chemotherapy with 5-fluorouracil and cisplatin in advanced pancreatic cancer:a feasibility study.Am J Clin Oncol.2008,31(1):71-78.
Vaage J,Barber(?)-Guillem E,Abra R,et al.Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts.Cancer,1994,73(5):1478-1484.
Vaage J,Donovan D,Uster P,et al.Tumor uptake of doxorubicin in polyethylene glycol-coated liposomes and therapeutic effect against a xenografted human pancreatic carcinoma.Br J Cancer.1997;75(4):482-486.
陈卫东,张弘炜,范健.脂质体阿霉素对小鼠移植性肿瘤的治疗作用.现代医学,2002,30(6):358-360.
郜永顺,陈孝平,李开艳,丁磊,吴在德.人肝癌组织裸鼠原位种植模型体内筛选化疗药物可行性研究.肿瘤基础与临床.2006,19(4):282-284.
张弘炜,范健.脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究.铁道医学,2000,28(6):362-364.
周平红,秦新裕.脂质体阿霉素及其靶向治疗研究进展.中国临床医学,2002,9(4):331-334.
周平红,姚礼庆,秦新裕,等.磁性阿霉素脂质体靶向治疗裸鼠大肠癌的实验研究.中华医学杂志,2003,83(23):2073-2076.
Allendorf JD,Lauerman M,Bill A,et al.Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma:feasibility,efficacy,and survival.J Gastrointest Surg.2008;12(1):91-100.
Ammori JB,Colletti LM,Zalupski MM,et al.Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas.J Gastrointest Surg 2003;7:766-72.
Bakkevold K,Arnesjo B,Dahl O,Kambestad B.Adjuvant combination chemotherapy (AMF)following radical resection of carcinoma of the pancreas and papilla of vater-results of a controlled,prospective,randomised multicentre study.Eur J Can 1993;29A:698-703.
Burris 3rd HA,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial.J Clin Oncol 1997;6:2403-13.
Cleary SP,Gryfe R,Guindi M,et al.Prognostic factors in resected pancreatic adenocarcinoma:analysis of actual 5-year survivors.J Am Coll Surg 2004;198:722-31.
Cress RD,Yin DX,Clarke L,Bold R,Holly EA.Survival among patients with adenocarcinoma of the pancreas:a population-based study(United States).Cancer Causes Control 2006;17:403-9.
Douglass H.Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer.Cancer 1987;59:2006-10.
Greer SE,Pipas JM,Sutton JE,et al.Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma.J Am Coll Surg.2008;206(3):451-7.
Hoffman JP,Lipsitz S,Pisansky T,Weese JL,Solin L,Benson Ⅲ AB.Phase Ⅱ Trial of Preoperative radiation therapy and chemotherapy for patients with localized,resectable adenocarcinoma of the pancreas:an Eastern Cooperative Oncology Group Study.J Clin Oncol 1998;16:317-23.
Ishikawa O,Ohigashi H,Imaoka S,et al.Is the long-term survival rate improved by preoperative irradiation prior to Whipple's procedure for adenocarcinoma of the pancreatic head? Arch Surg 1994;129:1075-80.
Jemal A,Siegel R,Ward E,Murray T,Xu J,Thun MJ.Cancer statistics,2007.CA Cancer J Clin 2007;57:43-66.
Kaiser M,Ellenberg S.Pancreatic cancenadjuvant combined radiation and chemotherapy following curative resection.Arch Surg 1985;120:899-903.
Kim HJ,Czischke K,Brennan MF,et al.Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? J Gastrointest Surg 2002;6(5):763-9.
Klinkenbijl J,Jeekel J,Sahmoud T,et al.Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region.Phase Ⅲ trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group.Ann Surg 1999;230:776-84.
Kosuge T,Kiuchi T,Mukai K,Kakizoe T.A multicenter randomised controlled trial to evaluate the effect of adjuvant cisplatin and 5-Fluorouracil therapy after curative resection in cases of pancreatic cancer.Jpn J Clin Oncol 2006;36:159-65.
Moutardier V,Magnin V,Turrini O,et al.Assessment of pathologic response after preoperative chemotherapy and surgery in pancreatic adenocarcinoma.Int J Radiat Oncol Biol Phys 2004;60:437-43.
Neoptolemos J,Dunn J,Stocken D,et al.Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer:a randomised controlled trial.Lancet 2001;358:1576-85.
Neoptolemos J,Stocken D,Freiss H,et al.A randomised trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med 2004;350:1200-10.
Oettle H,Post S,Neuhaus P,et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer:a randomized controlled trial.JAMA 2007;297:267-77.
Pisters PWT,Wolff RA,Crane CH,Evans DB.Combined modality treatment for operable pancreatic adenocarcinoma.Oncology 2005;19(3).Pisters PWT,Abbruzzese JL,Janjan NA,et al.Rapid-fractionation preoperative chemoradiation,pancreaticodudenectomy,and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.J Clin Oncol 1998;16:3843-50.
Regine WF,Winter KW,Abrams R,et al.RTOG 9704 a phase Ⅲ study of adjuvant pre and post chemoradiation 5FU vs.gemcitabine for resected pancreatic adenocarcinoma.J Clin Oncol 2005;24(18S).[abstract 4007].
Stessin AM,Meyer JE,Sherr DL.Neoadjuvant Radiation is Associated with Improved Survival in Patients with Resectable Pancreatic Cancer:An Analysis of Data from the Surveillance,Epidemiology,and End Results (SEER)Registry.Int J Radiat Oncol Biol Phys.2008 Jun 4.
Safran H,Dipetrillo T,Iannitti D,et al.Gemcitabine,paclitaxel and radiation for locally advanced pancreatic cancer:a phase I trial.Int J Radiat Oncol Biol Phys 2002;54:137-41.
Safran H,Moore T,Iannitti D,et al.Paclitaxel and concurrent radiation for locally advanced pancreatic cancer.Int J Radiat Oncol Biol Phys 2001;49:1275-9.
Stocken D,Buchler M,Dervenis C,et al.Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer.Br J Cancer 2005;92:1372-81.
Sperti C,Pasquali C,PiccoliA,Pedrazzoli S.Recurrence after resection for ductal adenocarcinoma of the pancreas.World J Surg 1997;21:195-200.
Takada T,Amano H,Yasuda H,et al.Is postoperative adjuvant chemotherapy useful for gall bladder carcinoma? A phase Ⅲ multicentre prospective randomised controlled trial in patients with resected pancreaticobiliary carcinoma.Cancer 2002;95:1685-95.
Varadhachary GR,Tamm EP,Abbruzzese JL,et al.Borderline resectable pancreatic cancer:definitions,management and role of preoperative therapy.Ann Surg Oncol 2006;13:1035-46.
Vento P,Mustonen H,Joensuu T,et al.Impact of preoperative chemoradiotherapy on survival in patients with resectable pancreatic cancer.World J Gastroenterol.2007;13(21):2945-51.
White RR,Hurwitz HI,Morse MA,et al.Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.Ann Surg Oncol 2001;8:758-65.
Wolff RA,Evans DB,Crane CH,etal.Initial results of a preoperative gemcitabine-based chemoradiation for respectable pancreatic adenocarcinoma.Proc Am Soc Clin Oncol 2002;21:130a(abstract516).
Yeo CJ,Cameron JL,Lillemoe KD,et al.Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma.Part 2.Randomized controlled trial evaluating survival,morbidity and mortality.Ann Surg 2002;236:355-66.