以纳米给药系统为载体的抗癌药物对喉鳞癌细胞的作用
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摘要
目的传统化疗给药存在着系统毒性问题,纳米给药系统是纳米技术在医学领域的应用成果,能够提高药物在靶部位的浓集,降低系统损伤。由于肿瘤的生长和转移与新生血管密切相关,抗肿瘤血管治疗已经成为研究热点。目前认为传统细胞毒性药物治疗联合应用抗肿瘤血管治疗具有显著的抗肿瘤效果。本课题对载有细胞毒性药物和肿瘤血管靶向药物的纳米给药系统应用于喉鳞癌细胞进行了研究。
本课题以紫杉醇(PTX)为肿瘤细胞毒性药物模型,以生物降解材料甲氧基聚乙二醇-聚乳酸-羟基乙酸(methoxy poly(ethylene glycol)-poly(lactide-co-glycolide),MPEG-PLOA)为载体,制备出具有缓释效应的紫杉醇MPEG-PLGA纳米粒(PTX-NPs),对其制备条件进行了筛选,检测了其理化性质,对人喉癌Hep-2细胞进行了细胞毒性实验和细胞摄取实验;以血管靶向制剂康普瑞汀A4(combretastatin A4,CA4)为肿瘤血管靶向药物模型,制备出了MPEG-DSPE修饰的CA4长循环脂质体(CA4 Lipo),筛选出CA4 Lipo的最佳制备处方,对其理化性质进行了考察;在裸鼠皮下建立Hep-2细胞肿瘤模型,分组尾静脉给予纳米制剂和注射液,对药效进行了比较。
方法1.对PTXNPs制备方法进行了筛选。考察了乳化溶剂蒸发法中,乳化剂聚乙烯醇(PVA)的分子量和浓度、MPEG-PLGA浓度、油水相比例、有机相的成分、投药量、超声时间、超声功率等单因素的影响,进行处方优化。对纳米粒的理化性质进行表征。在体外将不同浓度的PTX NPs、市售PTX注射液和不载药的空白NPs分别作用于Hep-2细胞24h、48h、和72h,MTT法检测细胞增殖抑制作用。以6-香豆素为纳米粒的荧光探针,制备6-香豆素MPEG-PLGA纳米粒,激光共聚焦荧光显微镜下观察Hep-2细胞对荧光纳米粒的摄取情况。对PTX NPs和PTX注射液在小鼠体内的急性毒性进行了对比。
2.采用成膜水化法制备了MPEG-DSPE修饰的肿瘤血管靶向药物CA4的长循环脂质体。通过对磷脂种类、卵磷脂胆固醇比例、药脂比和磷脂浓度进行单因素考察的基础上,进行正交实验设计优化处方,筛选出制备CA4 Lipo的最佳制备工艺条件,并对脂质体的体外性质进行了评价。
3.建立喉癌Hep-2细胞荷瘤裸鼠模型,分别进行纳米给药系统和注射液尾静脉给药治疗。随机分为:(1)PTX NPs 10mg/kg+CA4 Lipo 40mg/kg组,(2)PTX NPs组10mg/kg,(3)CA4 Lipo组40mg/kg,(4)PTX注射液组10mg/kg,(5)CA4溶液组40mg/kg,(6)PTX注射液10mg/kg+CA4溶液40mg/kg组,(7)生理盐水组。每6天给药一次,共3次。观察各组动物全身情况,肿瘤体积、瘤重,计算抑瘤率。
结果1.按照优化条件制得的PTXNPs平均粒径为153.3±41.7 nm,Zeta电位为-5.36 mV,载药量为5.35±0.75%,包封率为75.56±2.61%。透射电镜下观察纳米粒光滑圆整,差示扫描量热(DSC)、X射线粉末衍射(XRD)显示,PTX在纳米粒中以分子复合形式存在。体外释放实验显示,药物随时间呈双相性释放,前10天内释放较快,约为86%,25天时累计释放完全。细胞毒性实验显示,经PTXNPs与PTX注射液处理后,Hep-2细胞生长受抑,且均存在量效和时效关系,二者24、48、72h IC_(50)值未见明显差别,在低浓度短时间内(1-10nmol/l,24h),PTXNPs作用效果较PTX注射液强。空白MPEG-PLGA纳米粒无明显细胞毒性作用。细胞摄取实验发现,Hep-2细胞大量摄取载6-香豆素纳米粒。纳米粒进入细胞后,存在于细胞浆中。小鼠体内急性毒性实验表明,PTX NPs对动物的刺激性较小,动物不良反应轻,提示PTX NPs静脉注射安全性高于PTX注射液。
2.经过筛选,制备脂质体的优化处方为:卵磷脂、胆固醇和MPEG-DSPE的摩尔比为71:24:5,药脂摩尔比为1:10,水化后磷脂浓度为60 mmol/l。制得的脂质体平均粒径为113.4±40.6nm,包封率为71.20±0.31%,4℃冰箱放置7天,外观、粒径和包封率无明显变化。
3.给药18天后,各组间裸鼠重量无统计学差异。与生理盐水组相比,纳米给药系统中PTX NPs+CA4 Lipo组、PTX NPs组和CA4 Lipo组,肿瘤体积均显著减小(P＜0.05)。PTX NPs+CA4 Lipo组与PTX NPs组和CA4 Lipo组相比,肿瘤体积存在显著性差异(P＜0.05),PTX NPs+CA4 Lipo组肿瘤体积显著减小。PTX NPs+CA4 Lipo组肿瘤体积和瘤重比PTX+CA4注射液组均明显减小(P＜0.05)。PTXNPs组与PTX注射液组之间无显著性差异(P＞0.05)。PTX NPs+CA4 Lipo组瘤重比生理盐水组明显降低(P＜0.05)。PTX NPs+CA4 Lipo组抑瘤率最高,达65.03%。
结论采用纳米给药系统为载体,联合应用细胞毒性药物紫杉醇和肿瘤血管靶向药物CA4,能够降低药物的毒副作用,对喉癌Hep-2细胞裸鼠移植瘤具有较强的抑瘤效果。提示纳米靶向给药系统对喉癌化疗有应用前景。
Objective The nanoparticle delivery system,one of the outcomes and focuses of nanotechnology,can increase the regional drug concentration and reduce the systematic toxicity,which was usually caused by traditional drug delivery systems. Considering the important role of the tumor blood vessels in the tumor growth and metastasis,we set the purpose of the thesis to explore the effect of nanoparticle delivery system loaded with cytotoxic drug and vascular disrupting agent on the laryngeal cancer Hep-2 cells.
We used paclitaxel(PTX) as a model of cytotoxic drug,and incorporated it into biodegradable polymer-methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (MPEG-PLGA) to synthesize the controlled released paclitaxel-loaded MPEG-PLGA nanoparticles(PTX NPs).The NPs were prepared by emulsification-solvent evaporation method,and the preparation condition was optimized.The characterization,in vitro release profile of NPs was evaluated.The in vitro cytotoxicity and uptaken was investigated with the human laryngeal cancer Hep-2 cells.We also prepared and characterized MPEG-DSPE liposome system for combretastatin A4(CA4),which serves a model of vascular disrupting agents.To identify the in vivo efficacy of PTX and CA4 against laryngeal cancer,PTX NPs and CA4 liposme were intravenously injected into Hep-2 cell xenograft nude mice model, with PTX and CA4 parenteral solutions as comparison.
Methods 1.The NPs were prepared by emulsification-solvent evaporation method, the preparation conditions were optimized,such as the molecular weight and concentration of PVA,the concentration of MPEG-PLGA,the ratio of oil and water et. al..The nanoparticle was characterized by dynamic light scattering technique for size and size distribution,TEM for morphological properties,DSC and XRD for the formation properties.The drug loading efficiency,drug encapsulation efficiency and in vitro drug release kinetics were measured by high performance liquid chromatography(HPLC).To evaluate the in vitro cytotoxicity,PTX NPs,paclitaxel injection and blank MPEG-PLGA NPs at various concentrations were added to treat Hep-2 cells.And MPEG-PLGA NPs loaded with coumarin-6 were synthesized to investigate the intracellular uptake by Hep-2 cells.Visual evidence of NPs'uptake was obtained by laser scanning confocal microscope.The acute toxicity of PTX NPs was also test in mice compared with paclitaxel injection.
2.The PEGylated CA4 long-circulating liposomes were prepared by thin-film hydration method.The orthogonal test design was used to optimize the technology of preparation.In vitro characteristics of the MPEG-DSPE liposome were investigated.
3.BALB/c nude mice bearing Hep-2 laryngeal squamous cell cancer were randomly assigned into seven treatment groups:(1) PTX NPs(10mg/kg)+CA4 liposome (40mg/kg);(2) PTX NPs,10mg/kg;(3) CA4 liposome,40mg/kg;(4) paclitaxel injection,10mg/kg;(5) CA4 injetion,40mg/kg;(6) paclitaxel injection(10mg/kg)+ CA4 injection(40mg/kg);(7) Saline.All the animals were intravenously injected every six days for 3 times.The systemic toxic reactions,body weight,tumor size,and tumor weight and were observed.The tumor inhibition rate(IR) was calculated.
Results 1.The PTX NPs particle size and Zeta potential were around 153.3±41.7 nm and-5.36 mV.Transmission electron microscopy(TEM) showed the NPs were homogeneous and spherical in shape.Differential scanning calorimeters(DSC) and X-ray powder diffractogram(XRD) did not detect any crystalline drug in the NPs samples.The drug loading efficiency was(5.35±0.75)%and encapsulation efficiency was(75.56±2.61)%.In the in vitro drug release study,paclitaxel was released from the NPs in a slow but time-dependent manner.Both of the PTX NPs and paclitaxel injection inhibited Hep-2 cell growth in a dose-and time-dependent manner.The PTX NPs showed higher or comparable cytotoxicity and IC_(50) value against human laryngeal cancer cell Hep-2 versus the commercial Cremopher EL-based paclitaxel formulation.At low concentration and shorter time(1-10nmol/l,24h),the PTX NPs had higher cytotoxicity against paclitaxel injection.No significant cytotoxicity was observed in blank MPEG-PLGA NPs.For the intracellular uptake study,NPs entered the cells and gathered in the cytoplasm.In the safety test,little side effect was observed in the PTX NPs group.It was considered PTX NPs was better tolerant in mice than paclitaxel injection.
2.The optimized formulation ratio was SPC:Chol:MPEG-DSPE=71:24:5,drug to lipid ratio 1:10,and the optimized final total drug concentration at 60 mmol/l.The size distribution of the liposome was 113.4±40.6 nm and the entrapment efficiency was 71.20±0.31%.The prepared liposomes showed stable physicochemical properties when stored at 4℃for 7 days.
3.On the 18th day,there was no significant difference in body weight among all the groups.The tumor volume in PTX NPs+CA4 Lipo group,PTX NPs group and CA4 liposome group was significantly smaller than the saline group(P＜0.05).There was significant difference in the tumor volume between the PTX NPs+CA4 liposome group and the PTX NPs group(P＜0.05).Significance also can be seen between the PTX NPs+CA4 liposome group and the CA4 liposome group(P＜0.05).The tumor volume in the PTX NPs+CA4 liposome group was significantly smaller.The tumor volume and weight of the PTX NPs+CA4 liposome group was significantly smaller than the paclitaxel injection+CA4 injection group(P＜0.05).There was significant difference in tumor weight between the PTX NPs+CA4 liposome group and saline group.The tumor weight in PTX NPs group and PTX injection group was similar (P＞0.05).The tumor inhibition rate for the PTX NPs+CA4 liposome was 65.03%, which was the highest among the groups.
Conclusion Nanoparticle delivery system as carders for the small molecular VDAs-CA4 and the cytoxicity agent-paclitaxel,can significantly inhibit the Hep-2 tumor growth in nude mice and reduce the drug toxicity.Our study suggests that the nanoparticle targeting delivery system is prospective for laryngeal cancer chemotherapy.
本课题以紫杉醇(PTX)为肿瘤细胞毒性药物模型,以生物降解材料甲氧基聚乙二醇-聚乳酸-羟基乙酸(methoxy poly(ethylene glycol)-poly(lactide-co-glycolide),MPEG-PLOA)为载体,制备出具有缓释效应的紫杉醇MPEG-PLGA纳米粒(PTX-NPs),对其制备条件进行了筛选,检测了其理化性质,对人喉癌Hep-2细胞进行了细胞毒性实验和细胞摄取实验;以血管靶向制剂康普瑞汀A4(combretastatin A4,CA4)为肿瘤血管靶向药物模型,制备出了MPEG-DSPE修饰的CA4长循环脂质体(CA4 Lipo),筛选出CA4 Lipo的最佳制备处方,对其理化性质进行了考察;在裸鼠皮下建立Hep-2细胞肿瘤模型,分组尾静脉给予纳米制剂和注射液,对药效进行了比较。
方法1.对PTXNPs制备方法进行了筛选。考察了乳化溶剂蒸发法中,乳化剂聚乙烯醇(PVA)的分子量和浓度、MPEG-PLGA浓度、油水相比例、有机相的成分、投药量、超声时间、超声功率等单因素的影响,进行处方优化。对纳米粒的理化性质进行表征。在体外将不同浓度的PTX NPs、市售PTX注射液和不载药的空白NPs分别作用于Hep-2细胞24h、48h、和72h,MTT法检测细胞增殖抑制作用。以6-香豆素为纳米粒的荧光探针,制备6-香豆素MPEG-PLGA纳米粒,激光共聚焦荧光显微镜下观察Hep-2细胞对荧光纳米粒的摄取情况。对PTX NPs和PTX注射液在小鼠体内的急性毒性进行了对比。
2.采用成膜水化法制备了MPEG-DSPE修饰的肿瘤血管靶向药物CA4的长循环脂质体。通过对磷脂种类、卵磷脂胆固醇比例、药脂比和磷脂浓度进行单因素考察的基础上,进行正交实验设计优化处方,筛选出制备CA4 Lipo的最佳制备工艺条件,并对脂质体的体外性质进行了评价。
3.建立喉癌Hep-2细胞荷瘤裸鼠模型,分别进行纳米给药系统和注射液尾静脉给药治疗。随机分为:(1)PTX NPs 10mg/kg+CA4 Lipo 40mg/kg组,(2)PTX NPs组10mg/kg,(3)CA4 Lipo组40mg/kg,(4)PTX注射液组10mg/kg,(5)CA4溶液组40mg/kg,(6)PTX注射液10mg/kg+CA4溶液40mg/kg组,(7)生理盐水组。每6天给药一次,共3次。观察各组动物全身情况,肿瘤体积、瘤重,计算抑瘤率。
结果1.按照优化条件制得的PTXNPs平均粒径为153.3±41.7 nm,Zeta电位为-5.36 mV,载药量为5.35±0.75%,包封率为75.56±2.61%。透射电镜下观察纳米粒光滑圆整,差示扫描量热(DSC)、X射线粉末衍射(XRD)显示,PTX在纳米粒中以分子复合形式存在。体外释放实验显示,药物随时间呈双相性释放,前10天内释放较快,约为86%,25天时累计释放完全。细胞毒性实验显示,经PTXNPs与PTX注射液处理后,Hep-2细胞生长受抑,且均存在量效和时效关系,二者24、48、72h IC_(50)值未见明显差别,在低浓度短时间内(1-10nmol/l,24h),PTXNPs作用效果较PTX注射液强。空白MPEG-PLGA纳米粒无明显细胞毒性作用。细胞摄取实验发现,Hep-2细胞大量摄取载6-香豆素纳米粒。纳米粒进入细胞后,存在于细胞浆中。小鼠体内急性毒性实验表明,PTX NPs对动物的刺激性较小,动物不良反应轻,提示PTX NPs静脉注射安全性高于PTX注射液。
2.经过筛选,制备脂质体的优化处方为:卵磷脂、胆固醇和MPEG-DSPE的摩尔比为71:24:5,药脂摩尔比为1:10,水化后磷脂浓度为60 mmol/l。制得的脂质体平均粒径为113.4±40.6nm,包封率为71.20±0.31%,4℃冰箱放置7天,外观、粒径和包封率无明显变化。
3.给药18天后,各组间裸鼠重量无统计学差异。与生理盐水组相比,纳米给药系统中PTX NPs+CA4 Lipo组、PTX NPs组和CA4 Lipo组,肿瘤体积均显著减小(P＜0.05)。PTX NPs+CA4 Lipo组与PTX NPs组和CA4 Lipo组相比,肿瘤体积存在显著性差异(P＜0.05),PTX NPs+CA4 Lipo组肿瘤体积显著减小。PTX NPs+CA4 Lipo组肿瘤体积和瘤重比PTX+CA4注射液组均明显减小(P＜0.05)。PTXNPs组与PTX注射液组之间无显著性差异(P＞0.05)。PTX NPs+CA4 Lipo组瘤重比生理盐水组明显降低(P＜0.05)。PTX NPs+CA4 Lipo组抑瘤率最高,达65.03%。
结论采用纳米给药系统为载体,联合应用细胞毒性药物紫杉醇和肿瘤血管靶向药物CA4,能够降低药物的毒副作用,对喉癌Hep-2细胞裸鼠移植瘤具有较强的抑瘤效果。提示纳米靶向给药系统对喉癌化疗有应用前景。
Objective The nanoparticle delivery system,one of the outcomes and focuses of nanotechnology,can increase the regional drug concentration and reduce the systematic toxicity,which was usually caused by traditional drug delivery systems. Considering the important role of the tumor blood vessels in the tumor growth and metastasis,we set the purpose of the thesis to explore the effect of nanoparticle delivery system loaded with cytotoxic drug and vascular disrupting agent on the laryngeal cancer Hep-2 cells.
We used paclitaxel(PTX) as a model of cytotoxic drug,and incorporated it into biodegradable polymer-methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (MPEG-PLGA) to synthesize the controlled released paclitaxel-loaded MPEG-PLGA nanoparticles(PTX NPs).The NPs were prepared by emulsification-solvent evaporation method,and the preparation condition was optimized.The characterization,in vitro release profile of NPs was evaluated.The in vitro cytotoxicity and uptaken was investigated with the human laryngeal cancer Hep-2 cells.We also prepared and characterized MPEG-DSPE liposome system for combretastatin A4(CA4),which serves a model of vascular disrupting agents.To identify the in vivo efficacy of PTX and CA4 against laryngeal cancer,PTX NPs and CA4 liposme were intravenously injected into Hep-2 cell xenograft nude mice model, with PTX and CA4 parenteral solutions as comparison.
Methods 1.The NPs were prepared by emulsification-solvent evaporation method, the preparation conditions were optimized,such as the molecular weight and concentration of PVA,the concentration of MPEG-PLGA,the ratio of oil and water et. al..The nanoparticle was characterized by dynamic light scattering technique for size and size distribution,TEM for morphological properties,DSC and XRD for the formation properties.The drug loading efficiency,drug encapsulation efficiency and in vitro drug release kinetics were measured by high performance liquid chromatography(HPLC).To evaluate the in vitro cytotoxicity,PTX NPs,paclitaxel injection and blank MPEG-PLGA NPs at various concentrations were added to treat Hep-2 cells.And MPEG-PLGA NPs loaded with coumarin-6 were synthesized to investigate the intracellular uptake by Hep-2 cells.Visual evidence of NPs'uptake was obtained by laser scanning confocal microscope.The acute toxicity of PTX NPs was also test in mice compared with paclitaxel injection.
2.The PEGylated CA4 long-circulating liposomes were prepared by thin-film hydration method.The orthogonal test design was used to optimize the technology of preparation.In vitro characteristics of the MPEG-DSPE liposome were investigated.
3.BALB/c nude mice bearing Hep-2 laryngeal squamous cell cancer were randomly assigned into seven treatment groups:(1) PTX NPs(10mg/kg)+CA4 liposome (40mg/kg);(2) PTX NPs,10mg/kg;(3) CA4 liposome,40mg/kg;(4) paclitaxel injection,10mg/kg;(5) CA4 injetion,40mg/kg;(6) paclitaxel injection(10mg/kg)+ CA4 injection(40mg/kg);(7) Saline.All the animals were intravenously injected every six days for 3 times.The systemic toxic reactions,body weight,tumor size,and tumor weight and were observed.The tumor inhibition rate(IR) was calculated.
Results 1.The PTX NPs particle size and Zeta potential were around 153.3±41.7 nm and-5.36 mV.Transmission electron microscopy(TEM) showed the NPs were homogeneous and spherical in shape.Differential scanning calorimeters(DSC) and X-ray powder diffractogram(XRD) did not detect any crystalline drug in the NPs samples.The drug loading efficiency was(5.35±0.75)%and encapsulation efficiency was(75.56±2.61)%.In the in vitro drug release study,paclitaxel was released from the NPs in a slow but time-dependent manner.Both of the PTX NPs and paclitaxel injection inhibited Hep-2 cell growth in a dose-and time-dependent manner.The PTX NPs showed higher or comparable cytotoxicity and IC_(50) value against human laryngeal cancer cell Hep-2 versus the commercial Cremopher EL-based paclitaxel formulation.At low concentration and shorter time(1-10nmol/l,24h),the PTX NPs had higher cytotoxicity against paclitaxel injection.No significant cytotoxicity was observed in blank MPEG-PLGA NPs.For the intracellular uptake study,NPs entered the cells and gathered in the cytoplasm.In the safety test,little side effect was observed in the PTX NPs group.It was considered PTX NPs was better tolerant in mice than paclitaxel injection.
2.The optimized formulation ratio was SPC:Chol:MPEG-DSPE=71:24:5,drug to lipid ratio 1:10,and the optimized final total drug concentration at 60 mmol/l.The size distribution of the liposome was 113.4±40.6 nm and the entrapment efficiency was 71.20±0.31%.The prepared liposomes showed stable physicochemical properties when stored at 4℃for 7 days.
3.On the 18th day,there was no significant difference in body weight among all the groups.The tumor volume in PTX NPs+CA4 Lipo group,PTX NPs group and CA4 liposome group was significantly smaller than the saline group(P＜0.05).There was significant difference in the tumor volume between the PTX NPs+CA4 liposome group and the PTX NPs group(P＜0.05).Significance also can be seen between the PTX NPs+CA4 liposome group and the CA4 liposome group(P＜0.05).The tumor volume in the PTX NPs+CA4 liposome group was significantly smaller.The tumor volume and weight of the PTX NPs+CA4 liposome group was significantly smaller than the paclitaxel injection+CA4 injection group(P＜0.05).There was significant difference in tumor weight between the PTX NPs+CA4 liposome group and saline group.The tumor weight in PTX NPs group and PTX injection group was similar (P＞0.05).The tumor inhibition rate for the PTX NPs+CA4 liposome was 65.03%, which was the highest among the groups.
Conclusion Nanoparticle delivery system as carders for the small molecular VDAs-CA4 and the cytoxicity agent-paclitaxel,can significantly inhibit the Hep-2 tumor growth in nude mice and reduce the drug toxicity.Our study suggests that the nanoparticle targeting delivery system is prospective for laryngeal cancer chemotherapy.
引文
1 Department of Veterans Affairs Laryngeal Cancer Study Group.Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer[J].New Engl J Med,1991,324:1685-1690.
2 Laccourreye O,Brasnu D,Bassot V,et al.Cisplatin-fluorouracil exclusive chemotherapy for T1-T3N0 glotics squamous cell carcinoma complete clinical resonders:five-year results[J].J Clin Oncol,1996,14(8):2331-2336.
3 Spaulding MB,Fischer SG;Wolf GT,et al.Tumor response,toxicity,and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma[J].J Clin Oncol,1994,12(8):1592-1599
4 Laccourreye O,Veivers D,Bassot V,et al.Analysis of local recurrence in patients with selective TI-3N0M0 squamous cell carcinoma of the true vocal cord managed with a platinum-based chetherapy-alone regimen for cure[J].Ann Otol Rhinol Laryngol,2002,111(4):315-321.
5 Sledge G.,Miller K.Exploiting the hallmarks of cancer:the future conquest of breast cancer[J].Eur J Cancer,2003,39:1668-1675.
6 Teicher BA,Molecular targets and cancer therapeutics:discovery,development and clinical validation[J].Drug Resist Updat,2000,3:67-73.
7 Singh M,Shirley B,Bajwa K,et al.Controlled release of recombinant insulin-like growth factor from a novel formulation of polylactide-co-glycolide microparticles[J].J Control Release,2001,70(1-2):21-28
8 Parikh RH,Parikh JR,Dubey RR,et al.Poly(D,L-lactide-co-glycolide)microspheres containing 5-fluorouracil:optimization of process parameters[J].AAPS Pharm Sci Tech,2003,4:1-8.
9 Folkman J.Fighting cancer by attacking its blood supply[J].Sci Am,1996,275(3):150-154.
10 Folkman J.What is the evidence that tumors are angiogenesis dependent[J]? J.Natl.Cancer Inst,1990,82:4-6.
11 Folkman J.Seminars in Medicine of the Beth Israel Hospital,Boston.Clinical applications of research on angiogenesis[J].N Engl J Med,1995,333:1757-1763.
12 Siemann DW,Warrington KH,Horsman MR.Targeting tumor blood vessels:an adjuvant strategy for radiation therapy[J].Radiother Oncol,2000;57:5-12.
13 Chaplin D J,Dougherty GJ.Tumour vasculature as a target for cancer therapy[J]. Br J Cancer, 1999, 80:57-64.
14 Mayer RJ. Two steps forward in the treatment of colorectal cancer[J]. N Engl J Med, 2004, 350(23):2406-2408.
15 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizutmab plus irinotecan, flurorouracil, and leucovorin for metastatic colorectal cance [J]. N Engl J Med, 2004,350:2335-2342.
16 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent[J]. J Natl Cancer Inst, 1990, 82(15):1247-1259.
17 Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer[J]. Ann Oncol, 1998, 9(3): 327-329.
18 Tan EH, Khoo KS, Wee J, et al. Phase Ⅱ trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma[J]. Ann Oncol, 1999,10(2): 235-237.
19 Gelderblom H, Verweij J, Nooter K, et al. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation[J|. Eur J Cancer, 2001, 37 (13): 1590-1598.
20 Kloover JS, den Bakker MA, Gelderbolm H, et al. Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens[J]. Br J Cancer, 2004, 90: 304-305.
21 Feng X, Yuan YJ, Wu JC, et al. Synthesis and evaluation of water-soluable paclitaxel prodrugs[J]. Bioorg and Med Chem Lett, 2002,12(22):3301-3303.
22 Damen EW, Wiegerinck PH, Braamer L, et al. Paclitaxel esters and malic acid as prodrugs with improved water solubility[J]. Bioorg and Med Chem, 2000, 8 (2):427-432.
23 He L, Wang GL, Zhang Q, et al. An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation and pharmacokinetic profile[J]. Int J Pharm, 2003, 250(1):45-50.
24 Crosasso P, Ceruti M, Brusa P, et al. Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes[J]. J Control Release, 2000, 63(1-2):19-30.
25 Kim SC, Kim DW, Shim YH, et al. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy[J]. J Control Release, 2001, 72(1-3):191-202.
26 Fonseca C, Sim(?)es S, Gaspar R, et al. Paclitaxel-loaded PLGA nanoparticles: preparation, physiochemical characterization and in vitro anti-tumoral activity[J]. J Control Release, 2002, 83(2):273-286.
27 Mu L, Feng SS. A novel controlled release formulation for the anticancer drug paclitaxel(Taxol): PLGA nanoparticles containing vitamin E TPGS[J]. J Control Release, 2003, 86(1):33-48.
28 Xie M, Zhou L, Hu T, et al. Intratumoral delivery of paclitaxel-loaded poly(lactic-co-glycolic acid) microspheres for Hep-2 laryngeal squamous cell carcinoma xenografts[J]. Anticancer Drugs, 2007, 18(4):459-466.
29 Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57:1829-1834.
30 Horsman MR, Ehrnrooth E, Ladekarl M, et al. The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors[J]. Int J Radiat Oncol Biol Phys, 1998,42:895-898.
31 Tozer GM, Prise VE, Wilson J, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues[J]. Cancer Res, 1999, 59:1626-1634.
32 Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate[J]. Anticancer Res, 1999, 19:189-195.
33 Grosios K, Holwell SE, McGown AT, et al. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug[J]. Br J Cancer, 1999, 81:1318-1327.
34 Grosios K, Loadman PM, Swaine DJ, et al. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma[J]. Anticancer Res, 2000,20:229-233.
35 Griggs J, Metcalfe JC, Hesketh R. Targeting tumour vasculature: the development of combretastatin A4[J]. Lancet Oncol, 2001, 2:82-87.
36 Beauregard DA, Thelwall PE, Chaplin DJ, et al. Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status[J]. Br J Cancer, 1998, 77:1761-1767.
37 Siemann DW, Mercer E, Lepler S, et al. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy[J]. Int J Cancer, 2002,
38 Wildiers, H, Ahmed, B, Guetens, G, et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence[J]. Eur J Cancer, 2004,40(2):284-290.
39 Nelkin BD, Ball DW. Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma[J]. Oncol Rep, 2001, 8(l):157-160
40 Dong Y, Feng SS. Methoxy poly(ethylene glycol)-poly(lactide)(MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs[J]. Biomaterials. 2004(25):2843-2849.
41 Lambert G, Fattal E, Couvreur P. Nanoparticles systems for the delivery of antisense oligonucleotides[J]. Adv Drug Deliv Rev, 2001,47:99-112.
42 Feng SS, Mu L, Win KY, et al. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel[J]. Curr Med Chem. 2004,11,413-424.
43 Yang T, Cui FD, Choi MK, et al. Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation[J]. Int J Pharm, 2007,338:317-326.
44 Kim BS, Kim CS, Lee Km. The intracellular uptake ability of chitosan-coated poly (D, L-lactide-co-glycolide) nanoparticles[J]. Arch Pharm Res, 2008, 31(8):1050-1054.
45 Dong Y, Feng SS. In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherap [J]. Biomaterials 2007,28:4154-4160.
46 Nsereko S, Amiji M. Localized delivery of paclitaxel in solid tumors from biodegradable chitin microparticle formulations[J]. Biomaterials, 2002, 23:2723-2731.
47 Suh H, Jeong B, Rathi R, et al. Regulation of smooth muscle cell proliferation using paclitaxel-loaded poly(ethylene oxide)-poly(lactide/glycolide) nanospheres[J]. J Biomed Mater Res, 1998,42:331-338.
48 Mu L, Feng SS. Vitamin E TPGS used as emulsifier in the solvent evaporation extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol)[J]. J Control Rel, 2002, 80:129-144.
49 Zhang Z, Feng SS. Nanoparticles of poly (lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release[J].Biomaterials,2006,27:262-270.
50 Panyam J,Sahoo S,Prabha S,et al.Fluorescence and electron microscopy probes for cellular and tissue uptake of poly(D,L-lactide-co-glycolide)nanoparticles[J].Int J Pharm,2003,262:1-11.
51 Lu W,Wang J,She Z,Jiang X.Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle[J].J Control Release,2007,118:38-53.
52 Nihei Y,Suzuki M,Okano A,et al.Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumour therapy[J].Jpn J Cancer Res,1999,90:1387-1395.
53 平其能.现代药剂学[M].中国医药科技出版社,2001,588-623.
54 Torchilin VP,Trubetskoy VS.Which polymers can make nanoparticulate drug carriers long-circulating?[J].Adv Drug Deliv Rev,1995,16:141-155.
55 Yuan F,Dellian M,Fukumura D,et al.Vascular permeability in a human tumor xenograft:molecular size dependence and cutoff size[J].Cancer Res.1995,55:3752-3756.
56 Laginha K,Mumbengegwi D,Allen T.Liposomes targeted via two different antibodies:assay,B-cell binding and cytotoxicity[J].Biochim Biophys Acta,2005,1711:25-32.
57 Awasthi VD,Garcia D,Goins BA,et al.Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits[J].Int J Pharm,2003,253(1-2):121-132.
58 Nallamothu R,Wood GC,Pattilo CB,et al.A tumor vasculature targeted liposome delivery system for combretastatin A4:design,characterization,and in vitro evaluation[J].AAPS Pharm Sci Tech,2006,7(2):E 32.
59 Derenzini M,Montanaro L,Chilla A,et al.Evaluation of thymidylate synthase protein experssion by Westen blotting and immunohistochemisrty on human colon carcinoma xenografts in nude mice[J].J Histochem Cytochem,2002,50(12):1633-1640.
60 Yeung SC,She M,Yang H,et al.Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model[J].J Clin Endocrinol Metab.2007,92(8):2902-2909.
1 Folkman J. Fighting cancer by attacking its blood supply[J]. Sci Am, 1996, 275(3): 150-154.
2 Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003, 3:401-410.
3 Risau W. Mechanisms of angiogenesis[J]. Nature, 1997, 386:671-674.
4 Hanahan D, Christofori G, Naik P, et al. Transgenic mouse models of tumor angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models[J]. Eur J Cancer, 1996, 32A(14):2386-2393.
5 Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis[J]. Science, 1994,264:569-571.
6 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications[J]. Semin Oncol, 2002, 29:10-14.
7 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[J]. N Engl J Med, 2004, 350:2335-2342.
8 Ramaswamy B, Elias AD, Kelbick NT, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients[J]. Clin Cancer Res, 2006,12:3124-3129.
9 Sandier A, Gray R, Perry MC, et al. Paclitaxel-Carboplatin alone or with bevacizumab for non-small cell lung cancer[J]. N Engl J Med, 2006, 355:2542-2550.
10 Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer[J]. N Engl J Med, 2003, 349:427-434.
11 Quesada AR, Munoz-Chapuli R, Medina MA. Anti-angiogenic drugs: from bench to clinical trials[J]. Med Res Rev, 2006,26(4):483-530.
12 Monk BJ, Han E, Josephscowan CA, et al. Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer[J]. Gynecol Oncol, 2006,102(2):140-144.
13 Kindler HL, Friberg G, Singh DA, et al. Phase Ⅱ trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer[J]. J Clin Oncol, 2005, 23(31):8033-8040.
14 Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer[J]. Gynecol Oncol, 2006, 103 (2):489-493.
15 Griffin RJ, Williams BW, Wild R, et al. Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-drived growth factors suppresses tumor growth and enhances tumor radiation response [J]. Cancer Res, 2002, 62:1702-1706.
16 Davis DW, Takamori R, Raut CP, et al. Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668[J]. Clin Cancer Res, 2005, 11 (2):678-689.
17 Ratain MJ, Eisen T, Stadler WM. Phase Ⅱ placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma[J]. J Clin Oncol, 2006,24(16):2505-2512.
18 Motzer RJ, Hutson TE, Tomczak KP, et al. Phase Ⅲ randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN- α ) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC)[C]. ASCO Annual Meeting, 2006.
19 Motzer RJ, Hutson TE, Tomzak P, et al. Sunitinib vs Interferon Alfa in metastatic renal-cell carcinoma[J]. N Engl J Med. 2007,356:115-124.
20 Mauceri HJ, Hanna NN, Beckett MA, et al. Combined effects of angiostatin and ionizing radiation in antitumor therapy[J]. Nature, 1998, 394:287-291.
21 Hanna NN, Seetharam S, Mauceri HJ, et al. Antitumor interaction of short-courses endostatin and ionizing radiation[J]. Cancer J, 2000, 6:287-293.
22 Beattie GJ ,Smyth JF. Phase Ⅰ study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites[J]. Clin Cancer Res, 1998, 4(8): 1899-1902.
23 Steward WP. Marimastat (BB2516): Current status of development[J]. Cancer Chemother Pharmacol, 1999, 43:56-60.
24 Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase Ⅲ trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy : Eastern Cooperative Oncology Group trial E2196[J]. J Clin Oncol, 2004, 22 (23):4683-4690.
25 Kudelka AP, Verschraegen CF, Loyer E. Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470 letter[J]. N Engl med, 1998, 338(14):991-992.
26 Glode LM, Barqawi A, Crighton F, et al. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma[J]. Cancer, 2003, 98: 1643-1648.
27 Lau H, Yee D, Mackinnon J, et al. Concomitant low-dose cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN): Analysis of survival and toxicity[J]. ASCO Meeting Abstracts, 2004, 22: 5555.
28 Chiou HE, Wang TE, Wang YY, et al. Efficacy and safety of thalidomide in patients with hepatocellular carcinoma[J]. World J Gastroenterol, 2006, 21(43): 6955-6960.
29 Huang X, Molema G, King S, et al. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature[J]. Science, 1997, 275:547-550.
30 Blakey DC, Westwood FR, Walker M, et al. Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models[J]. Clin Cancer Res, 2002,8:1974-1983.
31 Ching LM, Goldsmith D, Joseph WR, et al. Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice[J]. Cancer Res, 1999, 59:3304-3307.
32 Konerding MA, Fait E, Gaumann A. 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon[J]. Br J Cancer, 2001, 84: 1354-1362.
33 Tozer GM, Lewis S, Michalowski A, et al. The relationship between regional variations in blood flow and histology in a transplanted rat fibrosarcoma[J]. Br J Cancer, 1990,61:250-257.
34 Denekamp J. Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy[J]. Br J Radiol, 1993, 66:181-196.
35 Burrows FJ, Thorpe PE. Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature[J]. Proc Natl Acad Sci USA, 1993,90:8996-9000.
36 Hill SA, Lonergan SJ, Denekamp J, et al. Vinca alkaloids: anti-vascular effects in a murine tumour[J]. Eur J Cancer, 1993,29A:1320-1324.
37 Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease[J]. Cancer, 2004,100(12):2491-2499.
38 Huang X, Bennett M, He J, et al. Anti-phosphatidylserine monoclonal antibody 3G4 enhances the antitumor effects of docetaxel against human breast cancer [Abstract 1498]. Proc Am Assoc Cancer Res, 2004,45.
39 Arora N, Masood R, Zheng T, et al. Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells[J]. Cancer Res, 1999, 59(1):183-188.
40 Veenendaal LM, Jin H, Ran S, et al. In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors[J]. Proc Natl Acad Sci USA, 2002, 99(12):7866-7871.
41 Matsuno F, Haruta Y, Kondo M, et al. Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies[J]. Clin Cancer Res, 1999, 5(2):371-382.
42 Corbett TH, Bissery MC, Wozniak A, et al. Activity of flavone acetic acid (NSC-347512) against solid tumors of mice[J]. Invest New Drugs, 1986, 4:207-220.
43 Kerr DJ, Kaye SB. Flavone acetic acid-preclinical and clinical activity[J]. Eur J Cancer Clin Oncol, 1989,25:1271-1272.
44 Lash CJ, Li AE, Rutland M, et al. Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs[J]. Br J Cancer, 1998, 78:439-445.
45 Ching LM, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid[J]. Br J Cancer, 2002, 86:1937-1942.
46 Pedley RB, Boden JA, Boden R, et al. Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents[J]. Cancer Res, 1996, 56:3293-3300.
47 Pedley RB, Sharma SK, Boxer GM, et al. Enhancement of antibodydirected enzyme prodrug therapy in colorectal xenografts by an antivascular agent[J]. Cancer Res, 1999, 59:3998-4003.
48 Chaplin DJ, Dougherty GJ. Tumour vasculature as a target for cancer therapy[J]. Br J Cancer, 1999, 80(suppl1):57-64.
49 Lin CM, Ho HH, Pettit GR, et al. Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin[J]. Biochemistry, 1998,28:6984-6991.
50 Pettit GR, Temple C, Narayanan VL, et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs[J]. Anticancer Drug Des, 1995,10:299-309.
51 Pettit GR, Singh SB, Hamel E, et al. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4[J]. Experientia, 1989, 45:209-211.
52 Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57:1829-1834.
53 Chaplin DJ, Pettit GR, Parkins CS, et al. Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents[J]. Br J Cancer Suppl, 1996, 27:S86-S88.
54 Hori K, Saito S. Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis[J]. Br J Cancer, 2003,89:1334-1344.
55 Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate[J]. Anticancer Res, 1999,19:189-195.
56 Grosios K, Holwell SE, McGown AT, et al. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug[J]. Br J Cancer, 1999, 81:1318-1327.
57 Grosios K, Loadman PM, Swaine DJ, et al. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma[J]. Anticancer Res, 2000, 20:229-233.
58 Griggs J, Metcalfe JC, Hesketh R. Targeting tumour vasculature: the development of combretastatin A4[J]. Lancet Oncol, 2001,2:82-87.
59 Horsman MR, Ehrnrooth E, Ladekarl M, et al. The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors[J]. Int J Radiat Oncol Biol Phys, 1998,42:895-898.
60 Tozer GM, Prise VE, Wilson J, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues[J]. Cancer Res, 1999, 59:1626-1634.
61 Beauregard DA, Thelwall PE, Chaplin DJ, et al. Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status[J]. Br J Cancer, 1998, 77:1761-1767.
62 Siemann DW, Mercer E, Lepler S, et al. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy[J]. Int J Cancer, 2002,
63 Wildiers H, Ahmed B, Guetens G, et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence[J]. Eur J Cancer, 2004,40:284-290.
64 Nelkin BD, Ball DW. Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma[J]. Oncology Reports, 2001, 8(1):157-160.
65 Stevenson JP, Rosen M, Sun W, et al. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow[J]. J Clin Oncol, 2003,21(23): 4428-4438.
66 Rustin GJ, Galbraith SM, Anderson H, et al. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results [J]. J Clin Oncol, 2003,21(15): 2815-2822.
67 Hill SA, Toze GM, Pettit GR, et al. Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi4503[J]. Anticancer Res, 2002, 22:1453-1458.
68 Davis PD, Dougherty GJ, Blakey DC, et al. ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature[J]. Cancer Res, 2002, 62:7247-7253.
69 Goertz DE, Yu JL, Kerbel RS, et al. High-frequency Doppler ultrasound monitors the effects of antivascular therapy on tumor blood flow[J]. Cancer Res, 2002, 62(22):6371-6375.
70 Beerepoot LV, Radema SA, Witteveen EO, et al. Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors[J]. J Clin Oncol, 2006, 24(10):1491-1498.
71 Hori K, Saito S, Nihei Y, et al. Antitumor effects due to irreversible stoppage of tumor tissue blood flow: evaluation of a novel combretastatin A-4 derivative, AC7700[J].Jpn J Cancer Res,1999,90:1026-1038.
72 Li L,Rojiani A,Siemann DW.Targeting the tumor vasculature with combretastatin A-4 disodium phosphate:effects on radiation therapy[J].Int J Radiat Oncol Biol Phys,1998,42:899-903.
73 Pedley RB,Hill SA,Boxer GM,et al.Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin A-4 3-O-phosphate[J].Cancer Res,2001,61:4716-4722.
2 Laccourreye O,Brasnu D,Bassot V,et al.Cisplatin-fluorouracil exclusive chemotherapy for T1-T3N0 glotics squamous cell carcinoma complete clinical resonders:five-year results[J].J Clin Oncol,1996,14(8):2331-2336.
3 Spaulding MB,Fischer SG;Wolf GT,et al.Tumor response,toxicity,and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma[J].J Clin Oncol,1994,12(8):1592-1599
4 Laccourreye O,Veivers D,Bassot V,et al.Analysis of local recurrence in patients with selective TI-3N0M0 squamous cell carcinoma of the true vocal cord managed with a platinum-based chetherapy-alone regimen for cure[J].Ann Otol Rhinol Laryngol,2002,111(4):315-321.
5 Sledge G.,Miller K.Exploiting the hallmarks of cancer:the future conquest of breast cancer[J].Eur J Cancer,2003,39:1668-1675.
6 Teicher BA,Molecular targets and cancer therapeutics:discovery,development and clinical validation[J].Drug Resist Updat,2000,3:67-73.
7 Singh M,Shirley B,Bajwa K,et al.Controlled release of recombinant insulin-like growth factor from a novel formulation of polylactide-co-glycolide microparticles[J].J Control Release,2001,70(1-2):21-28
8 Parikh RH,Parikh JR,Dubey RR,et al.Poly(D,L-lactide-co-glycolide)microspheres containing 5-fluorouracil:optimization of process parameters[J].AAPS Pharm Sci Tech,2003,4:1-8.
9 Folkman J.Fighting cancer by attacking its blood supply[J].Sci Am,1996,275(3):150-154.
10 Folkman J.What is the evidence that tumors are angiogenesis dependent[J]? J.Natl.Cancer Inst,1990,82:4-6.
11 Folkman J.Seminars in Medicine of the Beth Israel Hospital,Boston.Clinical applications of research on angiogenesis[J].N Engl J Med,1995,333:1757-1763.
12 Siemann DW,Warrington KH,Horsman MR.Targeting tumor blood vessels:an adjuvant strategy for radiation therapy[J].Radiother Oncol,2000;57:5-12.
13 Chaplin D J,Dougherty GJ.Tumour vasculature as a target for cancer therapy[J]. Br J Cancer, 1999, 80:57-64.
14 Mayer RJ. Two steps forward in the treatment of colorectal cancer[J]. N Engl J Med, 2004, 350(23):2406-2408.
15 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizutmab plus irinotecan, flurorouracil, and leucovorin for metastatic colorectal cance [J]. N Engl J Med, 2004,350:2335-2342.
16 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent[J]. J Natl Cancer Inst, 1990, 82(15):1247-1259.
17 Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer[J]. Ann Oncol, 1998, 9(3): 327-329.
18 Tan EH, Khoo KS, Wee J, et al. Phase Ⅱ trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma[J]. Ann Oncol, 1999,10(2): 235-237.
19 Gelderblom H, Verweij J, Nooter K, et al. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation[J|. Eur J Cancer, 2001, 37 (13): 1590-1598.
20 Kloover JS, den Bakker MA, Gelderbolm H, et al. Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens[J]. Br J Cancer, 2004, 90: 304-305.
21 Feng X, Yuan YJ, Wu JC, et al. Synthesis and evaluation of water-soluable paclitaxel prodrugs[J]. Bioorg and Med Chem Lett, 2002,12(22):3301-3303.
22 Damen EW, Wiegerinck PH, Braamer L, et al. Paclitaxel esters and malic acid as prodrugs with improved water solubility[J]. Bioorg and Med Chem, 2000, 8 (2):427-432.
23 He L, Wang GL, Zhang Q, et al. An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation and pharmacokinetic profile[J]. Int J Pharm, 2003, 250(1):45-50.
24 Crosasso P, Ceruti M, Brusa P, et al. Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes[J]. J Control Release, 2000, 63(1-2):19-30.
25 Kim SC, Kim DW, Shim YH, et al. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy[J]. J Control Release, 2001, 72(1-3):191-202.
26 Fonseca C, Sim(?)es S, Gaspar R, et al. Paclitaxel-loaded PLGA nanoparticles: preparation, physiochemical characterization and in vitro anti-tumoral activity[J]. J Control Release, 2002, 83(2):273-286.
27 Mu L, Feng SS. A novel controlled release formulation for the anticancer drug paclitaxel(Taxol): PLGA nanoparticles containing vitamin E TPGS[J]. J Control Release, 2003, 86(1):33-48.
28 Xie M, Zhou L, Hu T, et al. Intratumoral delivery of paclitaxel-loaded poly(lactic-co-glycolic acid) microspheres for Hep-2 laryngeal squamous cell carcinoma xenografts[J]. Anticancer Drugs, 2007, 18(4):459-466.
29 Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57:1829-1834.
30 Horsman MR, Ehrnrooth E, Ladekarl M, et al. The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors[J]. Int J Radiat Oncol Biol Phys, 1998,42:895-898.
31 Tozer GM, Prise VE, Wilson J, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues[J]. Cancer Res, 1999, 59:1626-1634.
32 Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate[J]. Anticancer Res, 1999, 19:189-195.
33 Grosios K, Holwell SE, McGown AT, et al. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug[J]. Br J Cancer, 1999, 81:1318-1327.
34 Grosios K, Loadman PM, Swaine DJ, et al. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma[J]. Anticancer Res, 2000,20:229-233.
35 Griggs J, Metcalfe JC, Hesketh R. Targeting tumour vasculature: the development of combretastatin A4[J]. Lancet Oncol, 2001, 2:82-87.
36 Beauregard DA, Thelwall PE, Chaplin DJ, et al. Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status[J]. Br J Cancer, 1998, 77:1761-1767.
37 Siemann DW, Mercer E, Lepler S, et al. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy[J]. Int J Cancer, 2002,
38 Wildiers, H, Ahmed, B, Guetens, G, et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence[J]. Eur J Cancer, 2004,40(2):284-290.
39 Nelkin BD, Ball DW. Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma[J]. Oncol Rep, 2001, 8(l):157-160
40 Dong Y, Feng SS. Methoxy poly(ethylene glycol)-poly(lactide)(MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs[J]. Biomaterials. 2004(25):2843-2849.
41 Lambert G, Fattal E, Couvreur P. Nanoparticles systems for the delivery of antisense oligonucleotides[J]. Adv Drug Deliv Rev, 2001,47:99-112.
42 Feng SS, Mu L, Win KY, et al. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel[J]. Curr Med Chem. 2004,11,413-424.
43 Yang T, Cui FD, Choi MK, et al. Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation[J]. Int J Pharm, 2007,338:317-326.
44 Kim BS, Kim CS, Lee Km. The intracellular uptake ability of chitosan-coated poly (D, L-lactide-co-glycolide) nanoparticles[J]. Arch Pharm Res, 2008, 31(8):1050-1054.
45 Dong Y, Feng SS. In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherap [J]. Biomaterials 2007,28:4154-4160.
46 Nsereko S, Amiji M. Localized delivery of paclitaxel in solid tumors from biodegradable chitin microparticle formulations[J]. Biomaterials, 2002, 23:2723-2731.
47 Suh H, Jeong B, Rathi R, et al. Regulation of smooth muscle cell proliferation using paclitaxel-loaded poly(ethylene oxide)-poly(lactide/glycolide) nanospheres[J]. J Biomed Mater Res, 1998,42:331-338.
48 Mu L, Feng SS. Vitamin E TPGS used as emulsifier in the solvent evaporation extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol)[J]. J Control Rel, 2002, 80:129-144.
49 Zhang Z, Feng SS. Nanoparticles of poly (lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release[J].Biomaterials,2006,27:262-270.
50 Panyam J,Sahoo S,Prabha S,et al.Fluorescence and electron microscopy probes for cellular and tissue uptake of poly(D,L-lactide-co-glycolide)nanoparticles[J].Int J Pharm,2003,262:1-11.
51 Lu W,Wang J,She Z,Jiang X.Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle[J].J Control Release,2007,118:38-53.
52 Nihei Y,Suzuki M,Okano A,et al.Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumour therapy[J].Jpn J Cancer Res,1999,90:1387-1395.
53 平其能.现代药剂学[M].中国医药科技出版社,2001,588-623.
54 Torchilin VP,Trubetskoy VS.Which polymers can make nanoparticulate drug carriers long-circulating?[J].Adv Drug Deliv Rev,1995,16:141-155.
55 Yuan F,Dellian M,Fukumura D,et al.Vascular permeability in a human tumor xenograft:molecular size dependence and cutoff size[J].Cancer Res.1995,55:3752-3756.
56 Laginha K,Mumbengegwi D,Allen T.Liposomes targeted via two different antibodies:assay,B-cell binding and cytotoxicity[J].Biochim Biophys Acta,2005,1711:25-32.
57 Awasthi VD,Garcia D,Goins BA,et al.Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits[J].Int J Pharm,2003,253(1-2):121-132.
58 Nallamothu R,Wood GC,Pattilo CB,et al.A tumor vasculature targeted liposome delivery system for combretastatin A4:design,characterization,and in vitro evaluation[J].AAPS Pharm Sci Tech,2006,7(2):E 32.
59 Derenzini M,Montanaro L,Chilla A,et al.Evaluation of thymidylate synthase protein experssion by Westen blotting and immunohistochemisrty on human colon carcinoma xenografts in nude mice[J].J Histochem Cytochem,2002,50(12):1633-1640.
60 Yeung SC,She M,Yang H,et al.Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model[J].J Clin Endocrinol Metab.2007,92(8):2902-2909.
1 Folkman J. Fighting cancer by attacking its blood supply[J]. Sci Am, 1996, 275(3): 150-154.
2 Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003, 3:401-410.
3 Risau W. Mechanisms of angiogenesis[J]. Nature, 1997, 386:671-674.
4 Hanahan D, Christofori G, Naik P, et al. Transgenic mouse models of tumor angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models[J]. Eur J Cancer, 1996, 32A(14):2386-2393.
5 Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis[J]. Science, 1994,264:569-571.
6 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications[J]. Semin Oncol, 2002, 29:10-14.
7 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[J]. N Engl J Med, 2004, 350:2335-2342.
8 Ramaswamy B, Elias AD, Kelbick NT, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients[J]. Clin Cancer Res, 2006,12:3124-3129.
9 Sandier A, Gray R, Perry MC, et al. Paclitaxel-Carboplatin alone or with bevacizumab for non-small cell lung cancer[J]. N Engl J Med, 2006, 355:2542-2550.
10 Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer[J]. N Engl J Med, 2003, 349:427-434.
11 Quesada AR, Munoz-Chapuli R, Medina MA. Anti-angiogenic drugs: from bench to clinical trials[J]. Med Res Rev, 2006,26(4):483-530.
12 Monk BJ, Han E, Josephscowan CA, et al. Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer[J]. Gynecol Oncol, 2006,102(2):140-144.
13 Kindler HL, Friberg G, Singh DA, et al. Phase Ⅱ trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer[J]. J Clin Oncol, 2005, 23(31):8033-8040.
14 Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer[J]. Gynecol Oncol, 2006, 103 (2):489-493.
15 Griffin RJ, Williams BW, Wild R, et al. Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-drived growth factors suppresses tumor growth and enhances tumor radiation response [J]. Cancer Res, 2002, 62:1702-1706.
16 Davis DW, Takamori R, Raut CP, et al. Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668[J]. Clin Cancer Res, 2005, 11 (2):678-689.
17 Ratain MJ, Eisen T, Stadler WM. Phase Ⅱ placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma[J]. J Clin Oncol, 2006,24(16):2505-2512.
18 Motzer RJ, Hutson TE, Tomczak KP, et al. Phase Ⅲ randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN- α ) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC)[C]. ASCO Annual Meeting, 2006.
19 Motzer RJ, Hutson TE, Tomzak P, et al. Sunitinib vs Interferon Alfa in metastatic renal-cell carcinoma[J]. N Engl J Med. 2007,356:115-124.
20 Mauceri HJ, Hanna NN, Beckett MA, et al. Combined effects of angiostatin and ionizing radiation in antitumor therapy[J]. Nature, 1998, 394:287-291.
21 Hanna NN, Seetharam S, Mauceri HJ, et al. Antitumor interaction of short-courses endostatin and ionizing radiation[J]. Cancer J, 2000, 6:287-293.
22 Beattie GJ ,Smyth JF. Phase Ⅰ study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites[J]. Clin Cancer Res, 1998, 4(8): 1899-1902.
23 Steward WP. Marimastat (BB2516): Current status of development[J]. Cancer Chemother Pharmacol, 1999, 43:56-60.
24 Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase Ⅲ trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy : Eastern Cooperative Oncology Group trial E2196[J]. J Clin Oncol, 2004, 22 (23):4683-4690.
25 Kudelka AP, Verschraegen CF, Loyer E. Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470 letter[J]. N Engl med, 1998, 338(14):991-992.
26 Glode LM, Barqawi A, Crighton F, et al. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma[J]. Cancer, 2003, 98: 1643-1648.
27 Lau H, Yee D, Mackinnon J, et al. Concomitant low-dose cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN): Analysis of survival and toxicity[J]. ASCO Meeting Abstracts, 2004, 22: 5555.
28 Chiou HE, Wang TE, Wang YY, et al. Efficacy and safety of thalidomide in patients with hepatocellular carcinoma[J]. World J Gastroenterol, 2006, 21(43): 6955-6960.
29 Huang X, Molema G, King S, et al. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature[J]. Science, 1997, 275:547-550.
30 Blakey DC, Westwood FR, Walker M, et al. Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models[J]. Clin Cancer Res, 2002,8:1974-1983.
31 Ching LM, Goldsmith D, Joseph WR, et al. Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice[J]. Cancer Res, 1999, 59:3304-3307.
32 Konerding MA, Fait E, Gaumann A. 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon[J]. Br J Cancer, 2001, 84: 1354-1362.
33 Tozer GM, Lewis S, Michalowski A, et al. The relationship between regional variations in blood flow and histology in a transplanted rat fibrosarcoma[J]. Br J Cancer, 1990,61:250-257.
34 Denekamp J. Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy[J]. Br J Radiol, 1993, 66:181-196.
35 Burrows FJ, Thorpe PE. Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature[J]. Proc Natl Acad Sci USA, 1993,90:8996-9000.
36 Hill SA, Lonergan SJ, Denekamp J, et al. Vinca alkaloids: anti-vascular effects in a murine tumour[J]. Eur J Cancer, 1993,29A:1320-1324.
37 Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease[J]. Cancer, 2004,100(12):2491-2499.
38 Huang X, Bennett M, He J, et al. Anti-phosphatidylserine monoclonal antibody 3G4 enhances the antitumor effects of docetaxel against human breast cancer [Abstract 1498]. Proc Am Assoc Cancer Res, 2004,45.
39 Arora N, Masood R, Zheng T, et al. Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells[J]. Cancer Res, 1999, 59(1):183-188.
40 Veenendaal LM, Jin H, Ran S, et al. In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors[J]. Proc Natl Acad Sci USA, 2002, 99(12):7866-7871.
41 Matsuno F, Haruta Y, Kondo M, et al. Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies[J]. Clin Cancer Res, 1999, 5(2):371-382.
42 Corbett TH, Bissery MC, Wozniak A, et al. Activity of flavone acetic acid (NSC-347512) against solid tumors of mice[J]. Invest New Drugs, 1986, 4:207-220.
43 Kerr DJ, Kaye SB. Flavone acetic acid-preclinical and clinical activity[J]. Eur J Cancer Clin Oncol, 1989,25:1271-1272.
44 Lash CJ, Li AE, Rutland M, et al. Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs[J]. Br J Cancer, 1998, 78:439-445.
45 Ching LM, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid[J]. Br J Cancer, 2002, 86:1937-1942.
46 Pedley RB, Boden JA, Boden R, et al. Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents[J]. Cancer Res, 1996, 56:3293-3300.
47 Pedley RB, Sharma SK, Boxer GM, et al. Enhancement of antibodydirected enzyme prodrug therapy in colorectal xenografts by an antivascular agent[J]. Cancer Res, 1999, 59:3998-4003.
48 Chaplin DJ, Dougherty GJ. Tumour vasculature as a target for cancer therapy[J]. Br J Cancer, 1999, 80(suppl1):57-64.
49 Lin CM, Ho HH, Pettit GR, et al. Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin[J]. Biochemistry, 1998,28:6984-6991.
50 Pettit GR, Temple C, Narayanan VL, et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs[J]. Anticancer Drug Des, 1995,10:299-309.
51 Pettit GR, Singh SB, Hamel E, et al. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4[J]. Experientia, 1989, 45:209-211.
52 Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57:1829-1834.
53 Chaplin DJ, Pettit GR, Parkins CS, et al. Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents[J]. Br J Cancer Suppl, 1996, 27:S86-S88.
54 Hori K, Saito S. Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis[J]. Br J Cancer, 2003,89:1334-1344.
55 Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate[J]. Anticancer Res, 1999,19:189-195.
56 Grosios K, Holwell SE, McGown AT, et al. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug[J]. Br J Cancer, 1999, 81:1318-1327.
57 Grosios K, Loadman PM, Swaine DJ, et al. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma[J]. Anticancer Res, 2000, 20:229-233.
58 Griggs J, Metcalfe JC, Hesketh R. Targeting tumour vasculature: the development of combretastatin A4[J]. Lancet Oncol, 2001,2:82-87.
59 Horsman MR, Ehrnrooth E, Ladekarl M, et al. The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors[J]. Int J Radiat Oncol Biol Phys, 1998,42:895-898.
60 Tozer GM, Prise VE, Wilson J, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues[J]. Cancer Res, 1999, 59:1626-1634.
61 Beauregard DA, Thelwall PE, Chaplin DJ, et al. Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status[J]. Br J Cancer, 1998, 77:1761-1767.
62 Siemann DW, Mercer E, Lepler S, et al. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy[J]. Int J Cancer, 2002,
63 Wildiers H, Ahmed B, Guetens G, et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence[J]. Eur J Cancer, 2004,40:284-290.
64 Nelkin BD, Ball DW. Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma[J]. Oncology Reports, 2001, 8(1):157-160.
65 Stevenson JP, Rosen M, Sun W, et al. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow[J]. J Clin Oncol, 2003,21(23): 4428-4438.
66 Rustin GJ, Galbraith SM, Anderson H, et al. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results [J]. J Clin Oncol, 2003,21(15): 2815-2822.
67 Hill SA, Toze GM, Pettit GR, et al. Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi4503[J]. Anticancer Res, 2002, 22:1453-1458.
68 Davis PD, Dougherty GJ, Blakey DC, et al. ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature[J]. Cancer Res, 2002, 62:7247-7253.
69 Goertz DE, Yu JL, Kerbel RS, et al. High-frequency Doppler ultrasound monitors the effects of antivascular therapy on tumor blood flow[J]. Cancer Res, 2002, 62(22):6371-6375.
70 Beerepoot LV, Radema SA, Witteveen EO, et al. Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors[J]. J Clin Oncol, 2006, 24(10):1491-1498.
71 Hori K, Saito S, Nihei Y, et al. Antitumor effects due to irreversible stoppage of tumor tissue blood flow: evaluation of a novel combretastatin A-4 derivative, AC7700[J].Jpn J Cancer Res,1999,90:1026-1038.
72 Li L,Rojiani A,Siemann DW.Targeting the tumor vasculature with combretastatin A-4 disodium phosphate:effects on radiation therapy[J].Int J Radiat Oncol Biol Phys,1998,42:899-903.
73 Pedley RB,Hill SA,Boxer GM,et al.Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin A-4 3-O-phosphate[J].Cancer Res,2001,61:4716-4722.