靶向EBV-LMP1 mRNA脱氧核酶治疗鼻咽癌的DCE-MRI临床和实验研究
|
摘要
新的抗肿瘤治疗已经从传统的细胞毒性药物向机制驱动的药物发展。鼻咽癌是我国常见的恶性肿瘤之一,靶向EBV-LMP1 mRNA脱氧核酶可能成为一类新型的鼻咽癌分子靶向治疗药物。影像学生物标志物在抗肿瘤药物的研发过程中的作用已经凸现。DCE-MRI可计算出定量动力学参数,反应肿瘤微循环改变。本文利用DCE-MRI从临床和动物模型两个层面探讨靶向EBV-LMP1 mRNA脱氧核酶对鼻咽癌的影响。
第一部分
目的：了解鼻咽癌DCE-MRI各参数的特点,并确定规范化的扫描技术和数据分析方法,为研究DCE-MRI监测鼻咽癌治疗效果打下基础。
方法：24例经病理确诊为低分化鳞状上皮细胞癌的鼻咽癌患者,均行常规MRI和DCE-MRI,采用nordicICE DCE软件对原始数据进行后处理,获得Ktrans、kep、Ve参数图,计算出肿瘤组织和翼外肌的动力学参数值。
结果：鼻咽癌肿瘤组织与翼外肌之间的Ktrans、kep、Ve值的差别均有统计学意义；鼻咽癌肿瘤组织Ktrans值95%可信区间0.1637(minute-1)～0.2164 (minute-1),而翼外肌Ktrans值95%可信区间为0.0745 (minute-1)～0.1020 (minute-1)鼻咽癌肿瘤组织Ktrans和kep存在正相关,Pearson相关系数为0.552(P值为0.009),Ve和kep存在负相关,Pearson相关系数为-0.473(P值为0.020)。
结论：采用规范的DCE-MRI扫描方法,以两腔室模型为基础,运用动脉流入函数动力学去卷积技术,可以获得DCE-MRI定量动力学参数(如Ktrans、kep、Ve)。鼻咽癌肿瘤组织与翼外肌之间的DCE-MRI定量动力学参数的差别主要是由于两者间的微循环不同造成；鼻咽癌肿瘤组织的DCE-MRI各动力学参数间存在一定的相关性。
第二部分
目的：采用建立的DCE-MRI方法评价联合运用靶向EBV-LMP1mRNA脱氧核酶和放射治疗对鼻咽癌血管改变和疗效。
方法：将24例EBV-LMP1表达阳性的鼻咽癌患者随机分为两组：综合治疗组(放疗+脱氧核酶)和单纯放疗组(放疗+生理盐水)。所有病例均分别于放疗前1-2天、放疗中(放射剂量为50Gy时)、放疗结束后1-2天内(放射剂量为70Gy)和放疗结束后3个月进行常规MRI和DCE-MRI扫描,获得不同时期肿瘤组织的Ktrans、Kep、Ve值和肿瘤体积,并计算出Ktrans值变化率和肿瘤体积变化率。
结果：综合治疗组从放疗中50Gy开始(包括放疗结束时、结束后3个月)肿瘤实质的Ktrans值、Kep值即与放疗前的差别有统计学意义,均低于放疗前；单纯放疗组放疗中50Gy,放疗结束时肿瘤实质的Ktrans值与放疗前的差别无统计学意义,直到放疗结束后3个月肿瘤实质Ktrans值与放疗前的差别才有统计学意义(P<0.05),而Kep值从放疗中50Gy开始即与放疗前的差别有统计学意义,均低于放疗前。随着治疗的进程,综合治疗组与单纯放疗组Ktans值变化率、肿瘤体积变化率的趋势相似,绝对值均逐渐增大,但到放疗结束后3个月时两组间的Ktans值变化率、体积变化率的差别有统计学意义(P<0.05)。
结论：单纯放射治疗或者联合运用靶向EBV-LMP1 mRNA脱氧核酶,鼻咽癌Ktrans值和Kep值均有下降,DCE-MRI定量动力学参数可无创性监测鼻咽癌治疗过程中肿瘤血管生成和血管通透性的改变,为及时评估疗效提供量化指标。放射治疗联合运用靶向EBV-LMP1 mRNA脱氧核酶,可促进肿瘤体积消退,并对肿瘤组织Ktrans值的下降起到一定作用。
第三部分
目的：利用DCE-MRI从动物体内水平探讨单独采用靶向EBV-LMP1脱氧核酶对鼻咽癌移植瘤血管通透性和血管生成的影响,并结合病理组织学和免疫组织化学试图明确其增强鼻咽癌裸鼠移植瘤放疗敏感性的分子机制。
方法：将鼻咽癌移植瘤裸鼠模型随机分为6小组：脱氧核酶组、寡核苷酸对照组、生理盐水组、低剂量放疗(5Gy)+脱氧核酶组、高剂量放疗(10Gy)+寡核苷酸组、高剂量放疗(10Gy)组,进行不同方式的干预。干预结束后均行常规MRI和DCE-MRI,获得移植瘤肿瘤组织的Ktrans值。移植瘤标本分别行VEGF和CD34免疫组化染色。
结果：脱氧核酶处理组与生理盐水组移植瘤肿瘤组织Ktrans值的差别有统计学意义(P<0.05),前者低于后者。脱氧核酶处理组VEGF表达为“±”,寡核苷酸对照组和生理盐水对照组VEGF表达为“+”,脱氧核酶处理组CD34表达为“±”,寡核苷酸对照组和生理盐水对照组CD34表达为“+”。低剂量放疗(5Gy)+脱氧核酶组、高剂量放疗(10Gy)+寡核苷酸组、高剂量放疗(10Gy)组间肿瘤实质Ktrans值的差别均无统计学意义。
结论：结合免疫组化和Ktrans值证实靶向EBV-LMP1 mRNA脱氧核酶导致鼻咽癌移植瘤血管生成和血管通透性下降,其病理生理学基础是靶向LMP1氧核酶在移植瘤内能够抑制VEGF的表达。Ktrans值可为探讨靶向EBV-LMP1 mRNA脱氧核酶放疗增敏机制提供依据。
The search for new anticancer therapeatics has shifted away from traditional cytotoxic agents to mechanism-driven drugs. Nasopharyngeal carcinoma (NPC) is one of common malignant tumors in China, and DNAzyme targeted to EBV-LMP1 mRNA may be one of the targeted molecular therapeatics for NPC. Imaging biomarkers are emerging and promising tools during the development of anticancer drugs. With the use of DCE-MRI, quantitative kinetic parameters can be generated as indicators for changes of tumor microcirculation. In this study, we attempt to investigate the effect of DNAzyme targeted to LMP1 mRNA on NPC in clinical research and animal model by using DCE-MRI.
PartⅠ
Objectives:To understand the quantitative kinetic parameters of DCE-MRI in NPC, and to standardize method of DCE-MRI scanning technology and data analysis, thus laying the foundation of DCE-MRI to monitor treatment effect of NPC.
Methods:24 NPC patients with pathologically diagnosed as poorly differentiated squamous cell carcinoma underwent conventional MRI and DCE-MRI. The nordicICE DCE software was used to post-process the raw data and obtain Ktrans、kep、Ve parameter map. The kinetic parameter values of NPC tumor tissue and lateral pterygoid muscle were calculated.
Results:There were statistically significant differences of Ktrans、 kep、Ve values between NPC tumor tissue and the lateral pterygoid muscle. The Ktrans value 95% CI of NPC tumor tissue was 0.1637 (minute-1) 0.2164 (minute-1), and the lateral pterygoid muscle was 0.0745 (minute-1)～0.1020 (minute-1). There was a positive correlation between Ktrans and kep value of NPC tumor tissue, and Pearson correlation coefficient was 0.552 (P= 0.009). Negative correlation existed between Ve and kep value of NPC tumor tissue, and Pearson correlation coefficient was -0.473 (P= 0.020).
Conclusion:Based on two-chamber kinetic model with arterial flow function deconvolution technology, standardized method of DCE-MRI scanning can generate quantitative kinetic parameters (Ktrans、kep、Ve). The differences of quantitative DCE-MRI kinetic parameters between NPC tumor tissue and lateral pterygoid muscle may be due to the difference of the microcirculation between the two. There are some correlation among the DCE-MRI kinetic parameters of NPC tumor tissue.
Part II
Objective:To investigate the effect and vascular changes following the treatment with combination of DNAzyme targeted to EBV-LMP1 mRNA with radiation therapy in NPC using DCE-MRI.
Methods:24 NPC patients with EBV-LMP1 positive expression were randomly divided into two groups:combined treatment group(radiotherapy +DNAzyme) and radiotherapy alone group (radiotherapy+saline). All patients underwent conventional MRI and DCE-MRI scans in 1 to 2 days before radiotherapy、during the radiotherapy (radiation dose of 50Gy)、at the end of radiotherapy (radiation dose of 70Gy) and 3 months after the end of radiotherapy. The Ktrans、kep、Ve values of NPC tumor tissue in different periods were obtained, and the change rates of Ktrans and tumor volume were calculated.
Results:In combined therapy group, there were statistically significant differences of the Ktrans value、Kep values of tumor tissue between pre-radiotherapy and post-radiotherapy(including during the radiotherapy、at the end of radiotherapy and 3 months after the end of radiotherapy), and the latter were lower than the former. In radiotherapy alone group, there was no significant difference of the Ktrans value of tumor tissue between pre-radiotherapy and during the radiotherapy、at the end of radiotherapy, and statistically significant difference of the Ktrans value only existed between pre-radiotherapy and 3 months after the end of radiotherapy(P<0.05); There were statistically significant differences of the Kep values of tumor tissue between pre-radiotherapy and post-radiotherapy(including during the radiotherapy、at the end of radiotherapy and 3 months after the end of radiotherapy), and the latter were lower than the former. During the process of treatment, there were a similar trend of the change rate of Ktrans、the change rate of tumor volume between combined therapy group and radiotherapy alone group, and the absolute values both increased gradually. However,3 months after the end of radiotherapy, the change rate of Ktrans、the change rate of tumor volume were significantly different between the two groups (P<0.05).
Conclusion:With radiotherapy alone or combined use of DNAzyme targeted to LMP1 mRNA, the Ktrans value, Kep value of NPC tumor tissue are both decreased. DCE-MRI quantitative kinetic parameters can be used to non-invasively assess the changes of tumor angiogenesis and vascular permeability during the treatment of NPC, providing timely quantitative indicators for the assessment of the efficacy. Combined with radiotherapy, the use of DNAzyme targeted to LMP1 mRNA can further promote tumor volume regression, and play a role in the decline of tumor tissue Ktrans.
PartⅢ
Objectives:To evaluate the effect of DNAzyme targeted to LMP1 mRNA on vascular permeability and angiogenesis of NPC xenograft in nude mice by using DCE-MRI, and to attempt to clarify the molecular mechanism of its enhancing radiosensitivity in NPC xenograft, combined with histopathology and immunohistochemistry.
Methods:The nude mice bearing NPC xenograft were randomly divided into 6 groups:DNAzyme treated group, oligonucleotide group, saline group, low dose radiation (5Gy)+DNAzyme group, high dose radiation (10Gy)+oligonucleotide group, high dose radiation (10Gy) group, and intervented respectively in different ways. All nude mice underwent routine MRI and DCE-MRI after interventions, and the Ktrans value of tumor tissue were obtained. Tumor specimens were immunostained with anti-human VEGF monoclonal antibody and CD34 antibody.
Results:There was a significant difference of the Ktrans value in xenografts tumor tissue between DNAzyme group and saline group (P <0.05), the former was lower than the latter. The VEGF expression in DNAzyme treated group is "±", but that in oligonucleotide group and saline group is "+". The CD34 expression in DNAzyme treated group is "±", but that in oligonucleotide group and saline group is "+". There were no significant difference of the Ktrans value in xenografts tumor tissue among Low-dose radiotherapy (5Gy)+DNAzyme group、high dose radiation (10Gy)+oligonucleotides group.
Conclusion:Combination of immunohistochemistry with Ktrans assessment can confirm that DNAzyme targeted to LMP1 mRNA could inhibit angiogenesis and decrease vascular permeability of NPC xenografts, and the pathophysiology basis is that DNAzyme targeted to LMP1 mRNA can inhibit the expression of VEGF. Ktrans can provide evidence for the mechanism of DNAzyme targeted to LMP1 mRNA enhancing radiosensitization.
第一部分
目的：了解鼻咽癌DCE-MRI各参数的特点,并确定规范化的扫描技术和数据分析方法,为研究DCE-MRI监测鼻咽癌治疗效果打下基础。
方法：24例经病理确诊为低分化鳞状上皮细胞癌的鼻咽癌患者,均行常规MRI和DCE-MRI,采用nordicICE DCE软件对原始数据进行后处理,获得Ktrans、kep、Ve参数图,计算出肿瘤组织和翼外肌的动力学参数值。
结果：鼻咽癌肿瘤组织与翼外肌之间的Ktrans、kep、Ve值的差别均有统计学意义；鼻咽癌肿瘤组织Ktrans值95%可信区间0.1637(minute-1)～0.2164 (minute-1),而翼外肌Ktrans值95%可信区间为0.0745 (minute-1)～0.1020 (minute-1)鼻咽癌肿瘤组织Ktrans和kep存在正相关,Pearson相关系数为0.552(P值为0.009),Ve和kep存在负相关,Pearson相关系数为-0.473(P值为0.020)。
结论：采用规范的DCE-MRI扫描方法,以两腔室模型为基础,运用动脉流入函数动力学去卷积技术,可以获得DCE-MRI定量动力学参数(如Ktrans、kep、Ve)。鼻咽癌肿瘤组织与翼外肌之间的DCE-MRI定量动力学参数的差别主要是由于两者间的微循环不同造成；鼻咽癌肿瘤组织的DCE-MRI各动力学参数间存在一定的相关性。
第二部分
目的：采用建立的DCE-MRI方法评价联合运用靶向EBV-LMP1mRNA脱氧核酶和放射治疗对鼻咽癌血管改变和疗效。
方法：将24例EBV-LMP1表达阳性的鼻咽癌患者随机分为两组：综合治疗组(放疗+脱氧核酶)和单纯放疗组(放疗+生理盐水)。所有病例均分别于放疗前1-2天、放疗中(放射剂量为50Gy时)、放疗结束后1-2天内(放射剂量为70Gy)和放疗结束后3个月进行常规MRI和DCE-MRI扫描,获得不同时期肿瘤组织的Ktrans、Kep、Ve值和肿瘤体积,并计算出Ktrans值变化率和肿瘤体积变化率。
结果：综合治疗组从放疗中50Gy开始(包括放疗结束时、结束后3个月)肿瘤实质的Ktrans值、Kep值即与放疗前的差别有统计学意义,均低于放疗前；单纯放疗组放疗中50Gy,放疗结束时肿瘤实质的Ktrans值与放疗前的差别无统计学意义,直到放疗结束后3个月肿瘤实质Ktrans值与放疗前的差别才有统计学意义(P<0.05),而Kep值从放疗中50Gy开始即与放疗前的差别有统计学意义,均低于放疗前。随着治疗的进程,综合治疗组与单纯放疗组Ktans值变化率、肿瘤体积变化率的趋势相似,绝对值均逐渐增大,但到放疗结束后3个月时两组间的Ktans值变化率、体积变化率的差别有统计学意义(P<0.05)。
结论：单纯放射治疗或者联合运用靶向EBV-LMP1 mRNA脱氧核酶,鼻咽癌Ktrans值和Kep值均有下降,DCE-MRI定量动力学参数可无创性监测鼻咽癌治疗过程中肿瘤血管生成和血管通透性的改变,为及时评估疗效提供量化指标。放射治疗联合运用靶向EBV-LMP1 mRNA脱氧核酶,可促进肿瘤体积消退,并对肿瘤组织Ktrans值的下降起到一定作用。
第三部分
目的：利用DCE-MRI从动物体内水平探讨单独采用靶向EBV-LMP1脱氧核酶对鼻咽癌移植瘤血管通透性和血管生成的影响,并结合病理组织学和免疫组织化学试图明确其增强鼻咽癌裸鼠移植瘤放疗敏感性的分子机制。
方法：将鼻咽癌移植瘤裸鼠模型随机分为6小组：脱氧核酶组、寡核苷酸对照组、生理盐水组、低剂量放疗(5Gy)+脱氧核酶组、高剂量放疗(10Gy)+寡核苷酸组、高剂量放疗(10Gy)组,进行不同方式的干预。干预结束后均行常规MRI和DCE-MRI,获得移植瘤肿瘤组织的Ktrans值。移植瘤标本分别行VEGF和CD34免疫组化染色。
结果：脱氧核酶处理组与生理盐水组移植瘤肿瘤组织Ktrans值的差别有统计学意义(P<0.05),前者低于后者。脱氧核酶处理组VEGF表达为“±”,寡核苷酸对照组和生理盐水对照组VEGF表达为“+”,脱氧核酶处理组CD34表达为“±”,寡核苷酸对照组和生理盐水对照组CD34表达为“+”。低剂量放疗(5Gy)+脱氧核酶组、高剂量放疗(10Gy)+寡核苷酸组、高剂量放疗(10Gy)组间肿瘤实质Ktrans值的差别均无统计学意义。
结论：结合免疫组化和Ktrans值证实靶向EBV-LMP1 mRNA脱氧核酶导致鼻咽癌移植瘤血管生成和血管通透性下降,其病理生理学基础是靶向LMP1氧核酶在移植瘤内能够抑制VEGF的表达。Ktrans值可为探讨靶向EBV-LMP1 mRNA脱氧核酶放疗增敏机制提供依据。
The search for new anticancer therapeatics has shifted away from traditional cytotoxic agents to mechanism-driven drugs. Nasopharyngeal carcinoma (NPC) is one of common malignant tumors in China, and DNAzyme targeted to EBV-LMP1 mRNA may be one of the targeted molecular therapeatics for NPC. Imaging biomarkers are emerging and promising tools during the development of anticancer drugs. With the use of DCE-MRI, quantitative kinetic parameters can be generated as indicators for changes of tumor microcirculation. In this study, we attempt to investigate the effect of DNAzyme targeted to LMP1 mRNA on NPC in clinical research and animal model by using DCE-MRI.
PartⅠ
Objectives:To understand the quantitative kinetic parameters of DCE-MRI in NPC, and to standardize method of DCE-MRI scanning technology and data analysis, thus laying the foundation of DCE-MRI to monitor treatment effect of NPC.
Methods:24 NPC patients with pathologically diagnosed as poorly differentiated squamous cell carcinoma underwent conventional MRI and DCE-MRI. The nordicICE DCE software was used to post-process the raw data and obtain Ktrans、kep、Ve parameter map. The kinetic parameter values of NPC tumor tissue and lateral pterygoid muscle were calculated.
Results:There were statistically significant differences of Ktrans、 kep、Ve values between NPC tumor tissue and the lateral pterygoid muscle. The Ktrans value 95% CI of NPC tumor tissue was 0.1637 (minute-1) 0.2164 (minute-1), and the lateral pterygoid muscle was 0.0745 (minute-1)～0.1020 (minute-1). There was a positive correlation between Ktrans and kep value of NPC tumor tissue, and Pearson correlation coefficient was 0.552 (P= 0.009). Negative correlation existed between Ve and kep value of NPC tumor tissue, and Pearson correlation coefficient was -0.473 (P= 0.020).
Conclusion:Based on two-chamber kinetic model with arterial flow function deconvolution technology, standardized method of DCE-MRI scanning can generate quantitative kinetic parameters (Ktrans、kep、Ve). The differences of quantitative DCE-MRI kinetic parameters between NPC tumor tissue and lateral pterygoid muscle may be due to the difference of the microcirculation between the two. There are some correlation among the DCE-MRI kinetic parameters of NPC tumor tissue.
Part II
Objective:To investigate the effect and vascular changes following the treatment with combination of DNAzyme targeted to EBV-LMP1 mRNA with radiation therapy in NPC using DCE-MRI.
Methods:24 NPC patients with EBV-LMP1 positive expression were randomly divided into two groups:combined treatment group(radiotherapy +DNAzyme) and radiotherapy alone group (radiotherapy+saline). All patients underwent conventional MRI and DCE-MRI scans in 1 to 2 days before radiotherapy、during the radiotherapy (radiation dose of 50Gy)、at the end of radiotherapy (radiation dose of 70Gy) and 3 months after the end of radiotherapy. The Ktrans、kep、Ve values of NPC tumor tissue in different periods were obtained, and the change rates of Ktrans and tumor volume were calculated.
Results:In combined therapy group, there were statistically significant differences of the Ktrans value、Kep values of tumor tissue between pre-radiotherapy and post-radiotherapy(including during the radiotherapy、at the end of radiotherapy and 3 months after the end of radiotherapy), and the latter were lower than the former. In radiotherapy alone group, there was no significant difference of the Ktrans value of tumor tissue between pre-radiotherapy and during the radiotherapy、at the end of radiotherapy, and statistically significant difference of the Ktrans value only existed between pre-radiotherapy and 3 months after the end of radiotherapy(P<0.05); There were statistically significant differences of the Kep values of tumor tissue between pre-radiotherapy and post-radiotherapy(including during the radiotherapy、at the end of radiotherapy and 3 months after the end of radiotherapy), and the latter were lower than the former. During the process of treatment, there were a similar trend of the change rate of Ktrans、the change rate of tumor volume between combined therapy group and radiotherapy alone group, and the absolute values both increased gradually. However,3 months after the end of radiotherapy, the change rate of Ktrans、the change rate of tumor volume were significantly different between the two groups (P<0.05).
Conclusion:With radiotherapy alone or combined use of DNAzyme targeted to LMP1 mRNA, the Ktrans value, Kep value of NPC tumor tissue are both decreased. DCE-MRI quantitative kinetic parameters can be used to non-invasively assess the changes of tumor angiogenesis and vascular permeability during the treatment of NPC, providing timely quantitative indicators for the assessment of the efficacy. Combined with radiotherapy, the use of DNAzyme targeted to LMP1 mRNA can further promote tumor volume regression, and play a role in the decline of tumor tissue Ktrans.
PartⅢ
Objectives:To evaluate the effect of DNAzyme targeted to LMP1 mRNA on vascular permeability and angiogenesis of NPC xenograft in nude mice by using DCE-MRI, and to attempt to clarify the molecular mechanism of its enhancing radiosensitivity in NPC xenograft, combined with histopathology and immunohistochemistry.
Methods:The nude mice bearing NPC xenograft were randomly divided into 6 groups:DNAzyme treated group, oligonucleotide group, saline group, low dose radiation (5Gy)+DNAzyme group, high dose radiation (10Gy)+oligonucleotide group, high dose radiation (10Gy) group, and intervented respectively in different ways. All nude mice underwent routine MRI and DCE-MRI after interventions, and the Ktrans value of tumor tissue were obtained. Tumor specimens were immunostained with anti-human VEGF monoclonal antibody and CD34 antibody.
Results:There was a significant difference of the Ktrans value in xenografts tumor tissue between DNAzyme group and saline group (P <0.05), the former was lower than the latter. The VEGF expression in DNAzyme treated group is "±", but that in oligonucleotide group and saline group is "+". The CD34 expression in DNAzyme treated group is "±", but that in oligonucleotide group and saline group is "+". There were no significant difference of the Ktrans value in xenografts tumor tissue among Low-dose radiotherapy (5Gy)+DNAzyme group、high dose radiation (10Gy)+oligonucleotides group.
Conclusion:Combination of immunohistochemistry with Ktrans assessment can confirm that DNAzyme targeted to LMP1 mRNA could inhibit angiogenesis and decrease vascular permeability of NPC xenografts, and the pathophysiology basis is that DNAzyme targeted to LMP1 mRNA can inhibit the expression of VEGF. Ktrans can provide evidence for the mechanism of DNAzyme targeted to LMP1 mRNA enhancing radiosensitization.
引文
[1]Kaban K, Herbst RS. Angiogenesis as a target for cancer therapy. Hematol Oncol Clin North Am,2002,16(5):1125-1171
[2]DuBois SG, Marina N, Glade-Bender J. Angiogenesis and vascular targeting in Ewing sarcoma:a review of preclinical and clinical data. Cancer,2010,116(3):749-757
[3]Grothey A, Ellis LM. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J,2008,14(3):170-177
[4]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol,1999, 3(4):500-509
[5]O'Connor JP, JacksonA, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular d isrupting agents. Br J Cancer,2007,96(2): 189-195
[6]Bajpai J, Gamanagatti S, Sharma MC, et al. Noninvasive imaging surrogate of angiogenesis in osteosarcoma. Pediatr Blood Cancer,2010,54(4):526-531
[7]Wu X, Jeong EK, Emerson L, et al. Noninvasive evaluation of antiangiogenic effect in a mouse tumor model by DCE-MRI with Gd-DTPA cystamine copolymers. Mol Pharm,2010,7(1):41-48
[8]Padhani AR, Leach MO. Antivascular cancer treatments:functional assessments by dynamic contrast-enhanced magnetic resonance imaging. Abdom Imaging,2005, 30(3):324-341
[9]PadhaniAR. Functional MRI for anticancer therapy assessment. Eu r J Cancer, 2002,38 (16):2116-2127
[10]Takashima S, Noguchi Y, Okumura T, et al. Dynamic MR imaging in the head and neck. Radiology,1993,189(3):813-819
[11]梁璟慧,李金高.动态增强MRI对鼻咽癌组织内乏氧和血管生成检测的研究.实用癌症杂志,2010,25(4)：350-353
[12]Tofts PS, Brix G, Buckley DL, et. al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[13]Preda A, Nov ikov V, M oglichM, e ta l. MRI monitoring of avastinTM antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging,2004,20 (5):865-873
[14]Tofts PS. Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging,1997,7(1):91-101
[15]Buckley DL. Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn Reson Med,2002,47(3):601-606
[16]Ferrier MC, Sarin H, Fung SH, et al. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia,2007, 9(7):546-555
[17]Eby PR, Partridge SC, White SW, et al. Metabolic and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)O water positron emission tomography blood flow in breast cancer. Acad Radiol,2008,15(10):1246-1254
[18]Niermann KJ, Fleischer AC, Huamani J, et al. Measuring tumor perfusion in control and treated murine tumors:correlation of microbubble contrastenhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. J Ultrasound Med,2007, 26(6):749-756
[19]Leach MO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[20]NCI, CIP, MR. Workshop on translational research in cancer:recommendations for MR measurement methods at 1.5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics aff ecting tumor vascular function. http://imaging.cancer.gov/ reportsandpublications/ReportsandPresentations/MagneticResonance (accessed Dec 11, 2006).
[21]Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic breast MR imaging:are signal intensity time course data useful for differential diagnosis of enhancing lesions. Radiology,1999,211(1):101-110
[22]Andrew van Hasselt. Nasopharyngeal carcinoma. Second edition, Hong Kong: The Chinese University Press,1999,127-160
[23]Daldrup HE, Shames DM, Husseini W, et al. Quantification of the extraction fraction for gadopentetate across breast cancer capillaries. Magn Reson Med,1998,40(4): 537-543
[24]Gribbestad IS, Nilsen G, Fjosne HE, et al. Comparative signal intensity measurements in dynamic gadolinium-enhanced MR mammography. J Magn Reson Imaging,1994,4(3):477-480
[25]Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab,1983,3(1):1-7
[26]Thukral A, Thomasson DM, Chow CK, et al. Inflammatory Breast Cancer: Dynamic Contrast-enhanced MRI in Patients Receiving Bevacizumab-Initial Experience. Radiology,2007,244(3):727-735
[27]Fluckiger JU, Schabel MC, Dibella EV. Model-based blind estimation of kinetic parameters in dynamic contrast enhanced (DCE)-MRI. Magn Reson Med,2009, 62(6):1477-1486
[28]Yang C, Karczmar GS, Medved M, et al. Reproducibility assessment of a multiple reference tissue method for quantitative dynamic contrast enhanced-MRI analysis. Magn Reson Med,2009,61(4):851-859
[29]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging, 2010,37(Suppl1):S164-182
[30]Larsson HBW, Stubgaard M, Frederiksen JL, et al. Quantitation of blood-brain barrier defect by magnetic resonance imaging and Gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magn Reson Med,1990,16(1):117-131
[31]Simpson NE, He Z, Evelhoch JL. Deuterium NMR tissue perfusion measurements using the tracer uptake approach:I. optimization of methods. Magn Reson Med,1999,42(1):42-52
[32]McIntyre DJO, Ludwig C, Pasan A, et al. A method for interleaved acquisition of a vascular input function for dynamic contrast-enhanced MRI in experimental rat tumours. NMR in biomedicine,2004,17(3):132-143
[33]Kim YR, Rebro KJ, Schmainda KM. Water exchange and inflow affect the accuracy of T1-GRE blood volume measurements:implications for the evaluation of tumor angiogenesis. Magn Reson Med,2002,47(6):1110-1120
[34]Yankeelov TE, Gore JC. Dynamic Contrast Enhanced Magnetic Resonance Imaging in Oncology:Theory, Data Acquisition, Analysis, and Examples. Curr Med Imaging Rev,2009,3(2):91-107
[35]Chen J, Yao J, Thomasson D. Automatic determination of arterial input function for dynamic contrast enhanced MRI in tumor assessment. Med Image Comput Comput Assist Interv,2008,11 (Pt 1):594-601
[36]Singh A, Rathore RK, Haris M, et al. Improved bolus arrival time and arterial input function estimation for tracer kinetic analysis in DCE-MRI. J Magn Reson Imaging, 2009,29(1):166-176
[37]Mayr NA, Yuh WT, Arnholt JC, et al. Pixel analysis of MR perfusion imaging in predict ing radiation therapy outcome in cervical cancer. J Magn Reson Imaging,2000, 12(6):1027-1033
[38]Padhan i AR, Mac Vicar DA, Gapinski CJ, et al. Effects of androgen deprivation treatment on prostate morphology and vascular permeability evaluated by magnet ic resonance imaging. Radiology,2001,218 (2):365-374
[39]UICC, International Union Against Cancer. TNM classification of malignant tumours,7th edition. New York:Wiley—Liss,2009:28-30
[40]Liu L, Liang S, Li L, et al. Prognostic impact of magnetic resonance imaging-detected cranial nerve involvement in nasopharyngeal carcinoma. Cancer, 2009,115(9):1995-2003
[41]Yu E, O'Sullivan B, Kim J, et al. Magnetic resonance imaging of nasopharyngeal carcinoma. Expert Rev Anticancer Ther,2010,10(3):365-375
[42]鲜军舫,王振常,罗德红.鼻咽癌影像学检查亟待进一步规范和深入研究.中华放射学杂志,2010,44(10)：1015-1018
[43]Yoshizako T, Wads A, Hayashi T, et al.Usefulness of diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging in the diagnosis of prostate transition-zone cancer. Acta Radiol,2008,49(10):1207-1213
[44]Kneeshaw PJ, Turnbull LW, Smith A, et al. Dynamic contrast enhanced magnetic resonance imaging aids the surgical management of invasive lobular breast cancer. Eur J Surg Oncol,2003,29(1):32-37
[45]Wei Huang, Xin Li, Elizabeth A, et al. The magnetic resonance shutter speed discriminates vascular properties of malignant and benign breast tumors in vivo. Proc Natl Acad Sci USA,2008,105(46):17943-17948
[46]张羲娥,刘中银,刘立志.鼻咽癌MRI动态增强特征观察研究.西南国防医药,2009,19(9)：887-890
[47]田丽,刘立志,范卫君.鼻咽癌MRI动态增强参数与微血管密度和血管内皮生长因子表达的相关性研究.中山大学学报(医学科学版),2009,30(3)：336-340
[48]丁忠祥,梁碧玲,沈君,等.动态增强MRI在鼻咽癌斜坡改变中的初步应用.临床放射学杂志,2005,24(8)：684-687
[49]钟镜联,梁碧玲,丁忠祥,等.应用MRI动态增强技术鉴别鼻咽癌放疗后枕骨斜坡纤维化与肿瘤复发.癌症,2006,25(1)：105-109
[50]阀松林,张文昌,苏友恒,等.鼻咽癌放疗后局部复发MRI动态增强灌注成像23例分析.中国误诊学杂志,2007,7(27)：6657-6658
[51]Bisdas S, Seitz O, Middendorp M, et al. An exploratory pilot study into the association between microcirculatory parameters derived by MRI-based pharmacokinetic analysis and glucose utilization estimated by PET-CT imaging in head and neck cancer. Eur Radiol,2010,20(10):2358-2366
[52]Whitcher B, Schmid VJ, Collins DJ, et al. A Bayesian hierarchical model for DCE-MRI to evaluate treatment response in a phase Ⅱ study in advanced squamous cell carcinoma of the head and neck. MAGMA.2011 Jan 4. [Epub ahead of print]
[53]Kim S, Loevner LA, Quon H, et al. Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging. AJNR,2010,31(2):262-268
[54]Jansen JF, Schoder H, Lee NY, et al. Noninvasive assessment of tumor microenvironment using dynamic contrast-enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography imaging in neck nodal metastases. Int J Radiat Oncol Biol Phys,2010,77(5):1403-1410
[55]Folkman J. Tumor Angiogenesis:Therapeutic Implications. N Engl J Med, 1971,285(8):11822-1186
[56]殷蔚伯,谷铣之.肿瘤放射治疗学.北京：中国协和医科大学出版社,2002.537-573
[1]刘海.鼻咽癌治疗的进展,川北医学院学报,2009,24(5)：417-420
[2]Lee N, Harris J, Garden AS, et al. Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma:radiation therapy oncology group phase Ⅱ trial 0225. J Clin Oncol,2009,27(22):3684-3690
[3]申志华,陈小毅,陈锦,等.EBV2LMP1上调Ezrin表达对鼻咽癌细胞转移潜能的影响.癌症,2008,27(2)：165-169
[4]Breaker RR, Joyce GF. A DNA enzyme that cleaves RNA. Chem Biol,1994, 1(4):223-229
[5]Banm DA, SilvermanSK. Deoxyribozymes:useful DNA catalysts in vitro and in vivo. Cell Mol Life Sci,2008,65(14):2156-2174
[6]Silverman SK.Catalytic DNA(Deoxyribozymes)for synthetie applications-current abilities and future prospects.Chem Commun,2008(30):3467-3485
[7]LuZX, MaXQ, YangLF et al. DNAzymes targeted to EBV-encoded latent membrane Protein-1 induce apoptosis and enhance radiosensitivity in nasopharyngeal carcinoma.Cancer Lett,2008,265(2):226-238
[8]Kaiser WA, Zeitler E. MR imaging of the breast:fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology,1989,170 (3 Pt 1):681-686
[9]van der Woude HJ, Verstraete KL, Hogendoorn PC, et al. Musculoskeletal tumors:does fast dynamic contrast-enhanced subtraction MR imaging contribute to the characterization? Radiology,1998,208(3):821-828
[10]Barentsz JO, Berger-Hartog O, Witjes JA, et al. Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology,1998,207(3):791-797
[11]Reddick WE, Taylor JS, Fletcher BD. Dynamic MR imaging (DEMRI) of microcirculation in bone sarcoma. J Magn Reson Imaging,1999,10(3):277-285
[12]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[13]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer,2007, 96(2):189-195
[14]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging. 2010,37,Suppl1:S164-182
[15]NCI, CIP, MR. Workshop on translational research in cancer:recommendations for MR measurement methods at 1-5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics affecting tumor vascular function. http://imaging.cancer.gov/ reportsandpublications/ReportsandPresentations/Magnetic Resonance (accessed Dec 11, 2006).
[16]Tofts PS, Brix G, Buckley DL, et. al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[17]Hawighorst H, Knapstein PG, Weikel W, et al. Angiogenesis of uterine cervical carcinoma:characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement. Cancer Res, 1997,57(21):4777-4786
[18]Tynninen O, Aronen HJ, Ruhala M, et al. MRI enhancement and microvascular density in gliomas. Correlation with tumor cell proliferation. Invest Radiol,1999,34(6): 427-434
[19]Buckley DL, Drew PJ, Mussurakis S, et al. Microvessel density of invasive breast cancer assessed by dynamic Gd-DTPA enhanced MRI. J Magn Reson Imaging, 1997,7(3):461-464
[20]O'Connor JP, Jackson A, Asselin MC, et al.Quantitative imaging biomarkers in the clinical development of targeted therapeutics:current and future perspectives. Lancet Oncol,2008,9(8):766-776
[21]Lankester KJ, Taylor JN, Stirling JJ, et al. Dynamic MRI for imaging tumor microvasculature:comparison of susceptibility and relaxivity techniques in pelvic tumors. J Magn Reson Imaging 2007,25(4):796-805
[22]Eby PR, Partridge SC, White SW, et al. Metabolic and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)0 water positron emission tomography blood flow in breast cancer. Acad Radiol 2008,15(10):1246-1254
[23]Niermann KJ, Fleischer AC, Huamani J, et al. Measuring tumor perfusion in control and treated murine tumors:correlation of microbubble contrastenhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. J Ultrasound Med 2007,26(6): 749-756
[24]Padhani AR. Dynamic contrast-enhanced MRI in clinical oncology:current status and future directions. J Magn Reson Imaging 2002,16(4):407-422
[25]Miller JC, Pien HH, Sahani D, et al. Imaging angiogenesis:applications and potential for drug development. J Natl Cancer Inst 2005,97(3):172-187
[26]Yankeelov TE, Gore JC. Dynamic Contrast Enhanced Magnetic Resonance Imaging in Oncology:Theory, Data Acquisition, Analysis, and Examples. Curr Med Imaging Rev,2009,3(2):91-107
[27]George ML, Dzik-Jurasz AS, et al. Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer. Br J Surg 2001,88(12):1628-1636
[28]Kim S, Loevner LA, Quon H, et al. Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging. AJNR,2010,31(2):262-268
[29]Workman P. Challenges of PK/PD measurements in modern drug development. Eur J Cancer,2002,38(16):2189-2193
[30]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol,1999, 3(4):500-509
[31]包尚联,徐萍芳.基于MRI的药物代谢动力学方法用于新药研发和药效评估的研究进展.中国仪器仪表学会医疗仪器分会第四次全国会员代表大会暨2009年学术年会论文集.
[32]Mross K, Drevs J, Muller M, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer,2005,41(9):1291-1299
[33]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of anti vascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging, 2010,37 (Suppl 1):S164-S182
[34]Baar J, Silverman P, Lyons J, et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res,2009,15(10):3583-3590
[35]Wilkinson ID, Jellineck DA, Levy D, et al. Dexamethasone and enhancing solitary cerebral mass lesions:alterations in perfusion and blood-tumor barrier kinetics shown by magnetic resonance imaging. Neurosurgery,2006,58(4):640-646
[36]O'Connor JP, Carano RA, Clamp AR, et al. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor:insights from imaging. Clin Cancer Res,2009,15(21):6674-6682
[37]Juan CJ, Chen CY, Jen YM, et al. Perfusion characteristics of late radiation injury ofparotid glands:quantitative evaluation with dynamic contrast-enhanced MRI Eur Radiol,2009,19(1):94-102
[38]Leach MO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[39]Egeland TAM, Simonsen TG, Gaustad JV, et al. Dynamic contrast-enhanced magnetic resonance imaging of tumors:preclinical validation of parametric images. Radiat Res,2009,172(3):339-347
[40]Gaustad JV, Benjaminsen IC, Ruud EBM, et al. Dynamic contrast enhanced magnetic resonance imaging of human melanoma xenografts with necrotic regions. J Magn Reson Imaging,2007,26(1):133-143
[41]Lu ZX, Ye M, Yan GR, et al. Effect of EBV LMP1 tageted DNAzymes on cell proliferation and apoptosis. Cancer Gene Ther,2005,12(7):647-654
[42]Yang L, Lu Z, Ma X, et al. A therapeutic approach to nasopharyngeal carcinomas by DNAzymes targeting EBV LMP-1 gene. Molecules,2010,15(9): 6127-6139
[43]Sourbron SP, Buckley DL. On the scope and interpretation of the Tofts models for DCE-MRI. Magn Reson Med,2011 Mar 7. doi:10.1002/mrm.22861. [Epub ahead of print]
[44]Port RE, Knopp MV, Hoffmann U, et al. Multicompartment analysis of gadolinium chelate kinetics:blood-tissue exchange in mammary tumors as monitored by dynamic MR imaging. J Magn Reson Imaging,1999,10(3):233-241
[45]Tofts PS. Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging,1997,7(1):91-101
[46]Buckley DL. Transcytolemmal water exchange and its affect on the determination of contrast agent concentration in vivo. Magn Reson Med,2002, 47(2):420-424
[1]Lu ZX, Ma XQ, Yang LF, et al. DNAzymes targeted to EBV-encoded latent membrane Protein-1 induce apoptosis and enhance radiosensitivity in nasopharyngeal carcinoma.Cancer Lett,2008,265(2):226-238
[2]Fromowitz FB, Viola MV, Chao S, et al. ras p21 expression in the progression of breast cancer. Hum Pathol,1987,18(12):1268-1275
[3]Marzola P, Degrassi A, Calderan L, et al. Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrastenhanced magnetic resonance imaging in an experimental model of colon carcinoma. Clin Cancer Res,2005,11(16): 5827-5832
[4]Salmon BA, Salmon HW, Siemann DW. Monitoring the treatment efficacy of the vascular disrupting agent CA4P. Eur J Cancer,2007,43(10):1622-1629
[5]Lee I, Kim DH, Sunar U, et al. The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer. In Vivo,2007,21(5):721-728
[6]Lee L, Sharma S, Morgan B, et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK):translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol,2006,57(6):761-771
[7]Yuh WTC, Mayr NA, Jarjoura D, et al. Predicting control of primary tumor and survival by DCE MRI during early therapy in cervical cancer. Invest Radiol,2009, 44(6):343-350
[8]Hawighorst H, Weikel W, Knapstein PG, et al. Angiogenic activity of cervical carcinoma:assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome. Clin Cancer Res,1998,4(10):2305-2312
[9]Zahra MA, Tan LT, Priest AN, et al. Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer. Int J Radiat Oncol Biol Phys,2009,74(3): 766-773
[10]Semple SIK, Harry VN, Parkin DE, et al. A combined pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging predicts response to chemoradiation in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys,2009,75(2):611-617
[11]Mussurakis S, Buckley DL, Horsman A. Dynamic MR imaging of invasive breast cancer:correlation with tumour grade and other histological factors. Br J Radiol,1997,70(833):446-451
[12]Cheng HL, Wallis C, Shou Z, et al. Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrastenhanced MRI using contrast agents of different molecular weights. J Magn Reson Imaging, 2007,25(1):137-145
[13]Ali MM, Janic B, Babajani-Feremi A, et al. Changes in vascular permeability and expression of different angiogenic factors following anti-angiogenic treatment in rat glioma. PLoS One,2010,5(1):e8727
[14]Gaustad JV, Benjaminsen IC, Ruud EBM, et al. Dynamic contrast enhanced magnetic resonance imaging of human melanoma xenografts with necrotic regions. J Magn Reson Imaging,2007,26(1):133-143
[15]Egeland TAM, Gaustad JV, Benjaminsen IC, et al. Assessment of fraction of hypoxic cells in human tumor xenografts with necrotic regions by dynamic contrast-enhanced MRI. Radiat Res,2008,169(6):689-699
[16]Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol, 2009,91(1):107-113
[17]Ellingsen C, Egeland TA, Galappathi K, et al. Dynamic contrast-enhanced magnetic resonance imaging of human cervical carcinoma xenografts: pharmacokinetic analysis and correlation to tumor histomo rphology. Radiother Oncol, 2010,97(2):217-224
[18]R(?)e K, Seierstad T, Kristian A, et al. Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions. Neoplasia,2010,12(10):818-825
[19]Weidner N. Tumoral vascularity as a prognostic factor in cancer patients:the evidence continues to grow. J Pathol,1998,184(2):119-122
[20]Hayes C, Padhani AR, Leach MO. Assessing changes intumour vascular function using dynamic contrast-enhanced magnetic resonance imaging. NMR Biomed,2002,15(2):154-163
[21]Weidner N. Tumour vascularity and proliferation:clear evidence of a close relationship. J Pathol,1999,189(3):297-299
[22]Folkman J, Shing Y. Angiogenesis. J Bio Chem,1992,267 (9):10931-10934
[23]Aref M, Chaudhari AR, Bailey KL, et al. Comparison of tumor histology to dynamic contrast enhanced magnetic resonance imaging-based physiological estimates. Magn Reson Imaging,2008,26(9):1279-1293
[24]Mayr NA, Hawighorst H, Yuh WT, et al. MR Microcirculation Assessment in Cervical Cancer Correlations wit h Histomorphological Tumor Markers and Clinical Outcome. J Magn Reson Imaging,1999,10 (3):267-276
[25]Knopp MV, Weiss E, Sinn HP, et al. Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging,1999,10(3):260-266
[26]Bhujwalla ZM, Artemov D, Natarajan K, et al. Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts. Neoplasia,2001,3(2):143-153
[27]Conrad C, Friedman H, Reardon D, et al. A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol (Meeting Abstracts),2004. Vol.22.
[28]Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol,2005,23 (24):5464-5473
[29]Lee L, Sharma S, Morgan B, et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK):translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol,2006,57(6):761-771
[30]Drevs J, Medinger M, Mross K, et al. Phase I clinical evaluation of AZD2171, a highly potent VEGF receptor tyrosine kinase inhibitor, in patients with advanced tumors. J Clin Oncol,2005 ASCO Annual Meeting Proceedings 2005, 23:3002.
[31]Jayson GC, Zweit J, Jackson A, et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody:implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst,2002,94(19):1484-1493
[32]Gossmann A, Helbich TH, Kuriyama N, et al. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme. J Magn Reson Imaging,2002,15(3):233-240
[33]Thomas A, Morgan B, Drevs J, et al. Pharmacodynamic results using dynamic contrast enhanced magnetic resonance imaging, of 2 phase 1 studies of the VEGF inhibitor PTK787/ZK 222584 in patients with liver metastases from colorectal cancer. In:Proceedings of American Society of Clinical Oncology.2001, San Francisco, ASCO, p A279
[34]Wang Z, Luo F, Li L, et al. STAT3 activation induced by Epstein-Barr virus latent membrane protein 1 causes vascular endothelial growth factor expression and cellular invasiveness via JAK3 And ERK signaling. Eur J Cancer,2010,46(16): 2996-3006
[35]柯霞,杨玉成,洪苏玲.靶向EBV-LMP1脱氧核酶对鼻咽癌裸鼠移植瘤生长的影响.第四军医大学学报,2009,30(22)：2599-2602
[1]Parkin DM, Bray F, Ferlay J, et al.Global cancer statistics.2002. CA Cancer JClin,2005,55(2):74-108
[2]Workman P. Challenges of PK/PD measurements in modern drug development.2002, Eur J Cancer,38(16):2189-2193
[3]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol, 1999,3(4):500-509
[4]FDA. Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products.2004, United States Food and Drug Administration
[5]Johnson JR, Williams G, Pazdur R. End points and UnitedStates Food and Drug Administration approval of oncology drugs.2003, J Clin Oncol,21 (7):1404-1411
[6]Congress U.S. Food and Drug Administration Modernization Act of 1997. Public Law 105-115,1997.105th Congress
[7]Karrison TG, Maitland ML, Stadler WM, et al. Design ofphase Ⅱ cancer trials using a continuous endpoint of change in tumor size:application to a study of sorafenib and erlotinib in non-small-cell lung cancer. J Natl Cancer Inst,2007,99 (19): 1455-1461.
[8]Roberts TG Jr, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA,2004, 292(17):2130-2140
[9]Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol,2005,23(24):5464-5473
[10]Morgan B, Thomas AL, Drevs J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases:results from two phase I studies. J Clin Oncol,2003,21(21):3955-3964
[11]Mross K, Drevs J, Muller M, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer,2005,41(9):1291-1299
[12]Thomas AL, Morgan B, Horsfield MA, et al. Phase Ⅰ study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK222584 administered twice daily in patients with advanced cancer. J Clin Oncol,2005, 23(18):4162-4171
[13]Rehman S, Jayson GC. Molecular imaging of antiangiogenic agents. Oncologist,2005,10(2):92-103
[14]Jayson G, Waterton JC. Applications of dynamic contrastenhanced MRI in oncology drug development. In:Jackson A, Parker GJM, Buckley DL, editors. Dynamic contrastenhanced magnetic resonance imaging in oncology. Berlin: Springer-Verlag,2005:281-97.
[15]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[16]O'Connor JP, Jackson A, Parker GJ, et al.DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195
[17]Tropres I, Grimault S, Vaeth A, et al. Vessel size imaging. Magn Reson Med, 2001,45(3):397-408
[18]Jayson GC, Parker GJM, Mullamitha S, et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol,2005,23(5):973-981
[19]Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol,2006,24(5):769-777
[20]Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res,2005,11(8):2785-2808
[21]Wells P, West C, Jones T, et al. Measuring tumor pharmacodynamic response using PET proliferation probes:the case for 2-[(11)C]-thymidine. Biochim Biophy Acta,2004,1705(2):91-102
[22]Weber WA. Chaperoning drug development with PET. J Nucl Med,2006, 47(5):735-737
[23]Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol,2006,24(20):3282-3292
[24]Chenevert TL, Meyer CR, Moffat BA, et al. Diffusion MRI:a new strategy for assessment of cancer therapeutic efficacy. Mol Imaging,2002, 1(4):336-343
[25]Dzik-Jurasz A, Domenig C, George M, et al. Diffusion MRI for prediction of response of rectal cancer to chemoradiation. Lancet,2002,360(9329):307-308
[26]Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell,2007,11(1):83-95
[27]Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol,2003, 21(7):1404-1411
[28]World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva:World Health Organization,1979.
[29]Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst,2000,92(3):205-216
[30]US Food and Drug Administration. Guidance for industry:clinical trial endpoints for the approval of cancer drugs and biologics.2007. http://www.fda.gov/cder/guidance/7478fnl.pdf (accessed July 10,2008).
[31]Karrison TG, Maitland ML, Stadler WM, et al. Design of phase II cancer trials using a continuous endpoint of change in tumor size:application to a study of sorafenib and erlotinib in non-small-cell lung cancer. J Natl Cancer Inst,2007,99(19): 1455-1461
[32]Thomas AL, Morgan B, Horsfi eld MA, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol,2005,23(18): 4162-4171
[33]Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol,2007,25(13):1760-1764
[34]van Persijn van Meerten EL, Gelderblom H, et al. RECIST revised: implications for the radiologist. A review article on the modified RECIST guideline.Eur Radiol,2010,20(6):1456-1467
[35]Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol,2007,25(13): 1753-1759
[36]Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol,2007,25(21):3045-3054
[37]Partridge SC, Gibbs JE, Lu Y, et al. MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival. Am J Roentgenol,2005,184(6):1774-1781
[38]Booth CM, Calvert AH, Giaccone G, et al.Design and conduct of phase II studies of targeted anticancer therapy:Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer,2008,44(1):25-29
[39]Hong X, Choi H, Loyer EM, et al.Gastrointestinal stromal tumor:role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics,2006,26(2):481-495
[40]Choi H. Response evaluation of gastrointestinal stromal tumors. Oncologist, 2008,13 Suppl 2:4-7.
[41]Bulusu VR, Jephcott CR, et al. RECIST and Choi criteria for response assessment (RA) in patients with inoperable and metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate. Cambridge GIST study group experience. Proc Am Soc Clin Oncol,2007,25 (suppl 18):abstr 10019.
[42]Miles KA, Young H, Chica SL, et al. Quantitative contrastenhanced computed tomography:is there a need for system calibration? Eur Radiol,2007,17(4): 919-926
[43]Mullamitha SA, Ton NC, Parker GJ, et al. Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res,2007,13(7):2128-2135
[44]Clamp AR, O'Connor JP, Mitchell CL, et al. Pharmacodynamic assessment of the anti-angiogenic and anti-vascular properties of bevacizumab by magnetic resonance imaging in metastatic colorectal carcinoma (CRC). Proc Am Soc Clin Oncol,2008,26 (suppl 18):(abstr 3546)
[45]Kaiser WA, Zeitler E. MR imaging of the breast:fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology,1989,170 (3 Pt 1):681-686
[46]Gribbestad IS, Nilsen G, Fjosne HE, et al. Comparative signal intensity measurements in dynamic gadolinium-enhanced MR mammography. J Magn Reson Imaging,1994,4(3):477-480
[47]Lankester KJ, Maxwell RJ, Pedley RB, et al. Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody,131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J Oncol,2007,30(2):453-460
[48]Lankester KJ, Taylor JN, Stirling JJ, et al. Dynamic MRI for imaging tumor microvasculature:comparison of susceptibility and relaxivity techniques in pelvic tumors. J Magn Reson Imaging,2007,25(4):796-805
[49]LeachMO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and anti-vascular therapies in early-stage clinical trials using magnetic resonance imaging:issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[50]Ah-See ML, Makris A, Taylor NJ, et al. Early changes in functional dynamic magnetic resonance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res,2008,14(20):6580-6589
[51]Thukral A, Thomasson DM, Chow CK, et al. Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab-initial experience. Radiology,2007,244(3):727-735
[52]Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab,1983,3(1):1-7
[53]Kety SS. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev,1951,3(1):1-41
[54]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195.
[55]Tofts P, Brix G, Buckley D, et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[56]Johnson JA, Wilson TA. A model for capillary exchange. Am J Physiol, 1966,210(6):1299-1303
[57]St Lawrence KS, Lee TY. An adiabatic approximation to the tissue homogeneity model for water exchange in the brain:Ⅰ. Theoretical derivation. J Cereb Blood Flow Metab,1998,18(12):1365-1377
[58]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[59]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195
[60]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging.2010,37, Suppl 1:S164-182
[61]NCI, CIP, MR. Workshop on translational research in cancer: recommendations for MR measurement methods at 1-5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics affecting tumor vascular function. http://imaging.cancer.gov/reportsandpublications/ReportsandPresentations/Magnetic Resonance (accessed Dec 11,2006).
[62]Conrad C, Friedman H, Reardon D, et al. A phase Ⅰ/Ⅱ trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol (Meeting Abstracts),2004. Vol.22.
[63]Flaherty KT, Rosen MA, Heitjan DF, et al. Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther,2008,7(4):496-501
[64]Nagashima T, Sakakibara M, Miyazaki M, et al.Dynamic enhanced MRI and chemosensitivity in breast cancer. Nippon Rinsho,2007,28,65 Suppl 6:530-534
[65]Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol,2006,24(5):769-777
[66]Galbraith SM, Rustin GJ, LodgeMA, et al. Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol,2002,20(18): 3826-3840
[67]Cheng HL. Dynamic contrast-enhanced MRI in oncology drug development. Curr Clin Pharmacol,2007,2(2):111-122
[68]Mross K, Fasol U, Frost A, et al. DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases:a randomized phase I study. J Angiogenes Res,2009,21,1:5
[69]Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol,2007,25(21):3045-3054
[70]Keunen O, Johansson M, Oudin A, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A, 2011,108(9):3749-3754
[71]Koehne C, Bajetta E, Lin E, et al. Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2). Proc Am Soc Clin Oncol, 2006,24 (suppl 18):(abstr 3508)
[72]Hillman GG, Singh-Gupta V, Al-Bashir AK, et al. Dynamic contrast-enhanced magnetic resonance imaging of sunitinib-induced vascular changes to schedule chemotherapy in renal cell carcinoma xenograft tumors.Transl Oncol, 2010,3(5):293-306.
[73]Jackson A. Analysis of dynamic contrast enhanced MRI. Br J Radiol,2004, 77(2):S154-66.
[74]Robinson SP, McIntyre DJ, Checkley D, et al. Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging. Br J Cancer, 2003,88(10):1592-1597
[75]McPhail LD, Griffi ths JR, Robinson SP. Assessment of tumor response to the vascular disrupting agents 5,6-dimethylxanthenone-4-acetic Acid or combretastatin-4-phosphate by intrinsic susceptibility magnetic resonance imaging. Int J Radiat Oncol Biol Phys,2007,69(4):1238-1245
[76]Donahue KM, Krouwer HG, Rand SD, et al. Utility of simultaneously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients. Magn Reson Med,2000,43(6):845-853
[77]Seddon BM, Payne GS, Simmons L, et al. Phase I pharmacokinetic and magnetic resonance spectroscopic study of the non-invasive hypoxia probe SR-4554. Proc Am Soc Clin Oncol,2002,21:91b.
[78]Hunjan S, Zhao D, Constantinescu A, et al. Tumour oximetry:demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning Prostate R3327-AT1 rat tumour. Int J Radiat Oncol Biol Phys,2001,49(4):1097-1108
[79]Zhao D, Constantinescu A, Hahn EW, et al. Tumour oxygen dynamics with respect to growth and respiratory challenge:investigation of the Dunning Prostate R3326-HI tumour. Radiat Res,2001,156(5 Pt 1):510-520
[80]McSheehy PM, Leach MO, Judson IR, et al. Metabolites of 29-fluoro-29-deoxy-D-glucose detected by 19F magnetic resonance spectroscopy in vivo predict response of murine RIF-1 tumors to 5-fluorouracil. Cancer Res,2000,60(8): 2122-2127.
[81]Patterson DM, Padhani AR, Collins DJ. Technology insight:water diffusion MRI-a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol, 2008,5(4):220-233
[82]Gerstner ER, Duda DG, di Tomaso E, et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol,2009, 6(4):229-236
[83]Pickles MD, Gibbs P, Lowry M, et al. Diffusion changes precede size reduction in neoadjuvant treatment of breast cancer. Magn Reson Imaging,2006, 24(7):843-847
[84]Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A,2004, 101(36):13306-13311
[85]Ahn BC. Molecular Imaging for Drug Discovery and Development. Curr Pharm Biotechnol,2011 Feb 21. [Epub ahead of print]
[86]Rudin M, Weissleder R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov,2003,2(2):123-131
[87]Chen K, Conti PS. Target-specific delivery of peptide-based probes for PET imaging.Adv Drug Deliv Rev,2010,62(11):1005-1022
[88].Weissleder R, Ntziachristos V. Shedding light onto live molecular targets. Nat Med,2003,9(1):123-128
[89]Postema M, Gilja OH.Contrast-enhanced and targeted ultrasound. World J Gastroenterol,2011,17(1):28-41
[90]Deshpande N, Pysz MA, Willmann JK. Molecular ultrasound assessment of tumor angiogenesis. Angiogenesis.2010,13(2):175-188
[91]Kelloff GJ, Krohn KA, Larson SM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res,2005 11(22):7967-7985
[2]DuBois SG, Marina N, Glade-Bender J. Angiogenesis and vascular targeting in Ewing sarcoma:a review of preclinical and clinical data. Cancer,2010,116(3):749-757
[3]Grothey A, Ellis LM. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J,2008,14(3):170-177
[4]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol,1999, 3(4):500-509
[5]O'Connor JP, JacksonA, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular d isrupting agents. Br J Cancer,2007,96(2): 189-195
[6]Bajpai J, Gamanagatti S, Sharma MC, et al. Noninvasive imaging surrogate of angiogenesis in osteosarcoma. Pediatr Blood Cancer,2010,54(4):526-531
[7]Wu X, Jeong EK, Emerson L, et al. Noninvasive evaluation of antiangiogenic effect in a mouse tumor model by DCE-MRI with Gd-DTPA cystamine copolymers. Mol Pharm,2010,7(1):41-48
[8]Padhani AR, Leach MO. Antivascular cancer treatments:functional assessments by dynamic contrast-enhanced magnetic resonance imaging. Abdom Imaging,2005, 30(3):324-341
[9]PadhaniAR. Functional MRI for anticancer therapy assessment. Eu r J Cancer, 2002,38 (16):2116-2127
[10]Takashima S, Noguchi Y, Okumura T, et al. Dynamic MR imaging in the head and neck. Radiology,1993,189(3):813-819
[11]梁璟慧,李金高.动态增强MRI对鼻咽癌组织内乏氧和血管生成检测的研究.实用癌症杂志,2010,25(4)：350-353
[12]Tofts PS, Brix G, Buckley DL, et. al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[13]Preda A, Nov ikov V, M oglichM, e ta l. MRI monitoring of avastinTM antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging,2004,20 (5):865-873
[14]Tofts PS. Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging,1997,7(1):91-101
[15]Buckley DL. Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn Reson Med,2002,47(3):601-606
[16]Ferrier MC, Sarin H, Fung SH, et al. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia,2007, 9(7):546-555
[17]Eby PR, Partridge SC, White SW, et al. Metabolic and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)O water positron emission tomography blood flow in breast cancer. Acad Radiol,2008,15(10):1246-1254
[18]Niermann KJ, Fleischer AC, Huamani J, et al. Measuring tumor perfusion in control and treated murine tumors:correlation of microbubble contrastenhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. J Ultrasound Med,2007, 26(6):749-756
[19]Leach MO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[20]NCI, CIP, MR. Workshop on translational research in cancer:recommendations for MR measurement methods at 1.5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics aff ecting tumor vascular function. http://imaging.cancer.gov/ reportsandpublications/ReportsandPresentations/MagneticResonance (accessed Dec 11, 2006).
[21]Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic breast MR imaging:are signal intensity time course data useful for differential diagnosis of enhancing lesions. Radiology,1999,211(1):101-110
[22]Andrew van Hasselt. Nasopharyngeal carcinoma. Second edition, Hong Kong: The Chinese University Press,1999,127-160
[23]Daldrup HE, Shames DM, Husseini W, et al. Quantification of the extraction fraction for gadopentetate across breast cancer capillaries. Magn Reson Med,1998,40(4): 537-543
[24]Gribbestad IS, Nilsen G, Fjosne HE, et al. Comparative signal intensity measurements in dynamic gadolinium-enhanced MR mammography. J Magn Reson Imaging,1994,4(3):477-480
[25]Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab,1983,3(1):1-7
[26]Thukral A, Thomasson DM, Chow CK, et al. Inflammatory Breast Cancer: Dynamic Contrast-enhanced MRI in Patients Receiving Bevacizumab-Initial Experience. Radiology,2007,244(3):727-735
[27]Fluckiger JU, Schabel MC, Dibella EV. Model-based blind estimation of kinetic parameters in dynamic contrast enhanced (DCE)-MRI. Magn Reson Med,2009, 62(6):1477-1486
[28]Yang C, Karczmar GS, Medved M, et al. Reproducibility assessment of a multiple reference tissue method for quantitative dynamic contrast enhanced-MRI analysis. Magn Reson Med,2009,61(4):851-859
[29]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging, 2010,37(Suppl1):S164-182
[30]Larsson HBW, Stubgaard M, Frederiksen JL, et al. Quantitation of blood-brain barrier defect by magnetic resonance imaging and Gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magn Reson Med,1990,16(1):117-131
[31]Simpson NE, He Z, Evelhoch JL. Deuterium NMR tissue perfusion measurements using the tracer uptake approach:I. optimization of methods. Magn Reson Med,1999,42(1):42-52
[32]McIntyre DJO, Ludwig C, Pasan A, et al. A method for interleaved acquisition of a vascular input function for dynamic contrast-enhanced MRI in experimental rat tumours. NMR in biomedicine,2004,17(3):132-143
[33]Kim YR, Rebro KJ, Schmainda KM. Water exchange and inflow affect the accuracy of T1-GRE blood volume measurements:implications for the evaluation of tumor angiogenesis. Magn Reson Med,2002,47(6):1110-1120
[34]Yankeelov TE, Gore JC. Dynamic Contrast Enhanced Magnetic Resonance Imaging in Oncology:Theory, Data Acquisition, Analysis, and Examples. Curr Med Imaging Rev,2009,3(2):91-107
[35]Chen J, Yao J, Thomasson D. Automatic determination of arterial input function for dynamic contrast enhanced MRI in tumor assessment. Med Image Comput Comput Assist Interv,2008,11 (Pt 1):594-601
[36]Singh A, Rathore RK, Haris M, et al. Improved bolus arrival time and arterial input function estimation for tracer kinetic analysis in DCE-MRI. J Magn Reson Imaging, 2009,29(1):166-176
[37]Mayr NA, Yuh WT, Arnholt JC, et al. Pixel analysis of MR perfusion imaging in predict ing radiation therapy outcome in cervical cancer. J Magn Reson Imaging,2000, 12(6):1027-1033
[38]Padhan i AR, Mac Vicar DA, Gapinski CJ, et al. Effects of androgen deprivation treatment on prostate morphology and vascular permeability evaluated by magnet ic resonance imaging. Radiology,2001,218 (2):365-374
[39]UICC, International Union Against Cancer. TNM classification of malignant tumours,7th edition. New York:Wiley—Liss,2009:28-30
[40]Liu L, Liang S, Li L, et al. Prognostic impact of magnetic resonance imaging-detected cranial nerve involvement in nasopharyngeal carcinoma. Cancer, 2009,115(9):1995-2003
[41]Yu E, O'Sullivan B, Kim J, et al. Magnetic resonance imaging of nasopharyngeal carcinoma. Expert Rev Anticancer Ther,2010,10(3):365-375
[42]鲜军舫,王振常,罗德红.鼻咽癌影像学检查亟待进一步规范和深入研究.中华放射学杂志,2010,44(10)：1015-1018
[43]Yoshizako T, Wads A, Hayashi T, et al.Usefulness of diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging in the diagnosis of prostate transition-zone cancer. Acta Radiol,2008,49(10):1207-1213
[44]Kneeshaw PJ, Turnbull LW, Smith A, et al. Dynamic contrast enhanced magnetic resonance imaging aids the surgical management of invasive lobular breast cancer. Eur J Surg Oncol,2003,29(1):32-37
[45]Wei Huang, Xin Li, Elizabeth A, et al. The magnetic resonance shutter speed discriminates vascular properties of malignant and benign breast tumors in vivo. Proc Natl Acad Sci USA,2008,105(46):17943-17948
[46]张羲娥,刘中银,刘立志.鼻咽癌MRI动态增强特征观察研究.西南国防医药,2009,19(9)：887-890
[47]田丽,刘立志,范卫君.鼻咽癌MRI动态增强参数与微血管密度和血管内皮生长因子表达的相关性研究.中山大学学报(医学科学版),2009,30(3)：336-340
[48]丁忠祥,梁碧玲,沈君,等.动态增强MRI在鼻咽癌斜坡改变中的初步应用.临床放射学杂志,2005,24(8)：684-687
[49]钟镜联,梁碧玲,丁忠祥,等.应用MRI动态增强技术鉴别鼻咽癌放疗后枕骨斜坡纤维化与肿瘤复发.癌症,2006,25(1)：105-109
[50]阀松林,张文昌,苏友恒,等.鼻咽癌放疗后局部复发MRI动态增强灌注成像23例分析.中国误诊学杂志,2007,7(27)：6657-6658
[51]Bisdas S, Seitz O, Middendorp M, et al. An exploratory pilot study into the association between microcirculatory parameters derived by MRI-based pharmacokinetic analysis and glucose utilization estimated by PET-CT imaging in head and neck cancer. Eur Radiol,2010,20(10):2358-2366
[52]Whitcher B, Schmid VJ, Collins DJ, et al. A Bayesian hierarchical model for DCE-MRI to evaluate treatment response in a phase Ⅱ study in advanced squamous cell carcinoma of the head and neck. MAGMA.2011 Jan 4. [Epub ahead of print]
[53]Kim S, Loevner LA, Quon H, et al. Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging. AJNR,2010,31(2):262-268
[54]Jansen JF, Schoder H, Lee NY, et al. Noninvasive assessment of tumor microenvironment using dynamic contrast-enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography imaging in neck nodal metastases. Int J Radiat Oncol Biol Phys,2010,77(5):1403-1410
[55]Folkman J. Tumor Angiogenesis:Therapeutic Implications. N Engl J Med, 1971,285(8):11822-1186
[56]殷蔚伯,谷铣之.肿瘤放射治疗学.北京：中国协和医科大学出版社,2002.537-573
[1]刘海.鼻咽癌治疗的进展,川北医学院学报,2009,24(5)：417-420
[2]Lee N, Harris J, Garden AS, et al. Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma:radiation therapy oncology group phase Ⅱ trial 0225. J Clin Oncol,2009,27(22):3684-3690
[3]申志华,陈小毅,陈锦,等.EBV2LMP1上调Ezrin表达对鼻咽癌细胞转移潜能的影响.癌症,2008,27(2)：165-169
[4]Breaker RR, Joyce GF. A DNA enzyme that cleaves RNA. Chem Biol,1994, 1(4):223-229
[5]Banm DA, SilvermanSK. Deoxyribozymes:useful DNA catalysts in vitro and in vivo. Cell Mol Life Sci,2008,65(14):2156-2174
[6]Silverman SK.Catalytic DNA(Deoxyribozymes)for synthetie applications-current abilities and future prospects.Chem Commun,2008(30):3467-3485
[7]LuZX, MaXQ, YangLF et al. DNAzymes targeted to EBV-encoded latent membrane Protein-1 induce apoptosis and enhance radiosensitivity in nasopharyngeal carcinoma.Cancer Lett,2008,265(2):226-238
[8]Kaiser WA, Zeitler E. MR imaging of the breast:fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology,1989,170 (3 Pt 1):681-686
[9]van der Woude HJ, Verstraete KL, Hogendoorn PC, et al. Musculoskeletal tumors:does fast dynamic contrast-enhanced subtraction MR imaging contribute to the characterization? Radiology,1998,208(3):821-828
[10]Barentsz JO, Berger-Hartog O, Witjes JA, et al. Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology,1998,207(3):791-797
[11]Reddick WE, Taylor JS, Fletcher BD. Dynamic MR imaging (DEMRI) of microcirculation in bone sarcoma. J Magn Reson Imaging,1999,10(3):277-285
[12]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[13]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer,2007, 96(2):189-195
[14]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging. 2010,37,Suppl1:S164-182
[15]NCI, CIP, MR. Workshop on translational research in cancer:recommendations for MR measurement methods at 1-5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics affecting tumor vascular function. http://imaging.cancer.gov/ reportsandpublications/ReportsandPresentations/Magnetic Resonance (accessed Dec 11, 2006).
[16]Tofts PS, Brix G, Buckley DL, et. al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[17]Hawighorst H, Knapstein PG, Weikel W, et al. Angiogenesis of uterine cervical carcinoma:characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement. Cancer Res, 1997,57(21):4777-4786
[18]Tynninen O, Aronen HJ, Ruhala M, et al. MRI enhancement and microvascular density in gliomas. Correlation with tumor cell proliferation. Invest Radiol,1999,34(6): 427-434
[19]Buckley DL, Drew PJ, Mussurakis S, et al. Microvessel density of invasive breast cancer assessed by dynamic Gd-DTPA enhanced MRI. J Magn Reson Imaging, 1997,7(3):461-464
[20]O'Connor JP, Jackson A, Asselin MC, et al.Quantitative imaging biomarkers in the clinical development of targeted therapeutics:current and future perspectives. Lancet Oncol,2008,9(8):766-776
[21]Lankester KJ, Taylor JN, Stirling JJ, et al. Dynamic MRI for imaging tumor microvasculature:comparison of susceptibility and relaxivity techniques in pelvic tumors. J Magn Reson Imaging 2007,25(4):796-805
[22]Eby PR, Partridge SC, White SW, et al. Metabolic and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)0 water positron emission tomography blood flow in breast cancer. Acad Radiol 2008,15(10):1246-1254
[23]Niermann KJ, Fleischer AC, Huamani J, et al. Measuring tumor perfusion in control and treated murine tumors:correlation of microbubble contrastenhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. J Ultrasound Med 2007,26(6): 749-756
[24]Padhani AR. Dynamic contrast-enhanced MRI in clinical oncology:current status and future directions. J Magn Reson Imaging 2002,16(4):407-422
[25]Miller JC, Pien HH, Sahani D, et al. Imaging angiogenesis:applications and potential for drug development. J Natl Cancer Inst 2005,97(3):172-187
[26]Yankeelov TE, Gore JC. Dynamic Contrast Enhanced Magnetic Resonance Imaging in Oncology:Theory, Data Acquisition, Analysis, and Examples. Curr Med Imaging Rev,2009,3(2):91-107
[27]George ML, Dzik-Jurasz AS, et al. Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer. Br J Surg 2001,88(12):1628-1636
[28]Kim S, Loevner LA, Quon H, et al. Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging. AJNR,2010,31(2):262-268
[29]Workman P. Challenges of PK/PD measurements in modern drug development. Eur J Cancer,2002,38(16):2189-2193
[30]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol,1999, 3(4):500-509
[31]包尚联,徐萍芳.基于MRI的药物代谢动力学方法用于新药研发和药效评估的研究进展.中国仪器仪表学会医疗仪器分会第四次全国会员代表大会暨2009年学术年会论文集.
[32]Mross K, Drevs J, Muller M, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer,2005,41(9):1291-1299
[33]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of anti vascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging, 2010,37 (Suppl 1):S164-S182
[34]Baar J, Silverman P, Lyons J, et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res,2009,15(10):3583-3590
[35]Wilkinson ID, Jellineck DA, Levy D, et al. Dexamethasone and enhancing solitary cerebral mass lesions:alterations in perfusion and blood-tumor barrier kinetics shown by magnetic resonance imaging. Neurosurgery,2006,58(4):640-646
[36]O'Connor JP, Carano RA, Clamp AR, et al. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor:insights from imaging. Clin Cancer Res,2009,15(21):6674-6682
[37]Juan CJ, Chen CY, Jen YM, et al. Perfusion characteristics of late radiation injury ofparotid glands:quantitative evaluation with dynamic contrast-enhanced MRI Eur Radiol,2009,19(1):94-102
[38]Leach MO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[39]Egeland TAM, Simonsen TG, Gaustad JV, et al. Dynamic contrast-enhanced magnetic resonance imaging of tumors:preclinical validation of parametric images. Radiat Res,2009,172(3):339-347
[40]Gaustad JV, Benjaminsen IC, Ruud EBM, et al. Dynamic contrast enhanced magnetic resonance imaging of human melanoma xenografts with necrotic regions. J Magn Reson Imaging,2007,26(1):133-143
[41]Lu ZX, Ye M, Yan GR, et al. Effect of EBV LMP1 tageted DNAzymes on cell proliferation and apoptosis. Cancer Gene Ther,2005,12(7):647-654
[42]Yang L, Lu Z, Ma X, et al. A therapeutic approach to nasopharyngeal carcinomas by DNAzymes targeting EBV LMP-1 gene. Molecules,2010,15(9): 6127-6139
[43]Sourbron SP, Buckley DL. On the scope and interpretation of the Tofts models for DCE-MRI. Magn Reson Med,2011 Mar 7. doi:10.1002/mrm.22861. [Epub ahead of print]
[44]Port RE, Knopp MV, Hoffmann U, et al. Multicompartment analysis of gadolinium chelate kinetics:blood-tissue exchange in mammary tumors as monitored by dynamic MR imaging. J Magn Reson Imaging,1999,10(3):233-241
[45]Tofts PS. Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging,1997,7(1):91-101
[46]Buckley DL. Transcytolemmal water exchange and its affect on the determination of contrast agent concentration in vivo. Magn Reson Med,2002, 47(2):420-424
[1]Lu ZX, Ma XQ, Yang LF, et al. DNAzymes targeted to EBV-encoded latent membrane Protein-1 induce apoptosis and enhance radiosensitivity in nasopharyngeal carcinoma.Cancer Lett,2008,265(2):226-238
[2]Fromowitz FB, Viola MV, Chao S, et al. ras p21 expression in the progression of breast cancer. Hum Pathol,1987,18(12):1268-1275
[3]Marzola P, Degrassi A, Calderan L, et al. Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrastenhanced magnetic resonance imaging in an experimental model of colon carcinoma. Clin Cancer Res,2005,11(16): 5827-5832
[4]Salmon BA, Salmon HW, Siemann DW. Monitoring the treatment efficacy of the vascular disrupting agent CA4P. Eur J Cancer,2007,43(10):1622-1629
[5]Lee I, Kim DH, Sunar U, et al. The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer. In Vivo,2007,21(5):721-728
[6]Lee L, Sharma S, Morgan B, et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK):translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol,2006,57(6):761-771
[7]Yuh WTC, Mayr NA, Jarjoura D, et al. Predicting control of primary tumor and survival by DCE MRI during early therapy in cervical cancer. Invest Radiol,2009, 44(6):343-350
[8]Hawighorst H, Weikel W, Knapstein PG, et al. Angiogenic activity of cervical carcinoma:assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome. Clin Cancer Res,1998,4(10):2305-2312
[9]Zahra MA, Tan LT, Priest AN, et al. Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer. Int J Radiat Oncol Biol Phys,2009,74(3): 766-773
[10]Semple SIK, Harry VN, Parkin DE, et al. A combined pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging predicts response to chemoradiation in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys,2009,75(2):611-617
[11]Mussurakis S, Buckley DL, Horsman A. Dynamic MR imaging of invasive breast cancer:correlation with tumour grade and other histological factors. Br J Radiol,1997,70(833):446-451
[12]Cheng HL, Wallis C, Shou Z, et al. Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrastenhanced MRI using contrast agents of different molecular weights. J Magn Reson Imaging, 2007,25(1):137-145
[13]Ali MM, Janic B, Babajani-Feremi A, et al. Changes in vascular permeability and expression of different angiogenic factors following anti-angiogenic treatment in rat glioma. PLoS One,2010,5(1):e8727
[14]Gaustad JV, Benjaminsen IC, Ruud EBM, et al. Dynamic contrast enhanced magnetic resonance imaging of human melanoma xenografts with necrotic regions. J Magn Reson Imaging,2007,26(1):133-143
[15]Egeland TAM, Gaustad JV, Benjaminsen IC, et al. Assessment of fraction of hypoxic cells in human tumor xenografts with necrotic regions by dynamic contrast-enhanced MRI. Radiat Res,2008,169(6):689-699
[16]Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol, 2009,91(1):107-113
[17]Ellingsen C, Egeland TA, Galappathi K, et al. Dynamic contrast-enhanced magnetic resonance imaging of human cervical carcinoma xenografts: pharmacokinetic analysis and correlation to tumor histomo rphology. Radiother Oncol, 2010,97(2):217-224
[18]R(?)e K, Seierstad T, Kristian A, et al. Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions. Neoplasia,2010,12(10):818-825
[19]Weidner N. Tumoral vascularity as a prognostic factor in cancer patients:the evidence continues to grow. J Pathol,1998,184(2):119-122
[20]Hayes C, Padhani AR, Leach MO. Assessing changes intumour vascular function using dynamic contrast-enhanced magnetic resonance imaging. NMR Biomed,2002,15(2):154-163
[21]Weidner N. Tumour vascularity and proliferation:clear evidence of a close relationship. J Pathol,1999,189(3):297-299
[22]Folkman J, Shing Y. Angiogenesis. J Bio Chem,1992,267 (9):10931-10934
[23]Aref M, Chaudhari AR, Bailey KL, et al. Comparison of tumor histology to dynamic contrast enhanced magnetic resonance imaging-based physiological estimates. Magn Reson Imaging,2008,26(9):1279-1293
[24]Mayr NA, Hawighorst H, Yuh WT, et al. MR Microcirculation Assessment in Cervical Cancer Correlations wit h Histomorphological Tumor Markers and Clinical Outcome. J Magn Reson Imaging,1999,10 (3):267-276
[25]Knopp MV, Weiss E, Sinn HP, et al. Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging,1999,10(3):260-266
[26]Bhujwalla ZM, Artemov D, Natarajan K, et al. Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts. Neoplasia,2001,3(2):143-153
[27]Conrad C, Friedman H, Reardon D, et al. A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol (Meeting Abstracts),2004. Vol.22.
[28]Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol,2005,23 (24):5464-5473
[29]Lee L, Sharma S, Morgan B, et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK):translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol,2006,57(6):761-771
[30]Drevs J, Medinger M, Mross K, et al. Phase I clinical evaluation of AZD2171, a highly potent VEGF receptor tyrosine kinase inhibitor, in patients with advanced tumors. J Clin Oncol,2005 ASCO Annual Meeting Proceedings 2005, 23:3002.
[31]Jayson GC, Zweit J, Jackson A, et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody:implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst,2002,94(19):1484-1493
[32]Gossmann A, Helbich TH, Kuriyama N, et al. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme. J Magn Reson Imaging,2002,15(3):233-240
[33]Thomas A, Morgan B, Drevs J, et al. Pharmacodynamic results using dynamic contrast enhanced magnetic resonance imaging, of 2 phase 1 studies of the VEGF inhibitor PTK787/ZK 222584 in patients with liver metastases from colorectal cancer. In:Proceedings of American Society of Clinical Oncology.2001, San Francisco, ASCO, p A279
[34]Wang Z, Luo F, Li L, et al. STAT3 activation induced by Epstein-Barr virus latent membrane protein 1 causes vascular endothelial growth factor expression and cellular invasiveness via JAK3 And ERK signaling. Eur J Cancer,2010,46(16): 2996-3006
[35]柯霞,杨玉成,洪苏玲.靶向EBV-LMP1脱氧核酶对鼻咽癌裸鼠移植瘤生长的影响.第四军医大学学报,2009,30(22)：2599-2602
[1]Parkin DM, Bray F, Ferlay J, et al.Global cancer statistics.2002. CA Cancer JClin,2005,55(2):74-108
[2]Workman P. Challenges of PK/PD measurements in modern drug development.2002, Eur J Cancer,38(16):2189-2193
[3]Buolamwini JK. Novel anticancer drug discovery. Curr Opin Chem Biol, 1999,3(4):500-509
[4]FDA. Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products.2004, United States Food and Drug Administration
[5]Johnson JR, Williams G, Pazdur R. End points and UnitedStates Food and Drug Administration approval of oncology drugs.2003, J Clin Oncol,21 (7):1404-1411
[6]Congress U.S. Food and Drug Administration Modernization Act of 1997. Public Law 105-115,1997.105th Congress
[7]Karrison TG, Maitland ML, Stadler WM, et al. Design ofphase Ⅱ cancer trials using a continuous endpoint of change in tumor size:application to a study of sorafenib and erlotinib in non-small-cell lung cancer. J Natl Cancer Inst,2007,99 (19): 1455-1461.
[8]Roberts TG Jr, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA,2004, 292(17):2130-2140
[9]Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol,2005,23(24):5464-5473
[10]Morgan B, Thomas AL, Drevs J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases:results from two phase I studies. J Clin Oncol,2003,21(21):3955-3964
[11]Mross K, Drevs J, Muller M, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer,2005,41(9):1291-1299
[12]Thomas AL, Morgan B, Horsfield MA, et al. Phase Ⅰ study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK222584 administered twice daily in patients with advanced cancer. J Clin Oncol,2005, 23(18):4162-4171
[13]Rehman S, Jayson GC. Molecular imaging of antiangiogenic agents. Oncologist,2005,10(2):92-103
[14]Jayson G, Waterton JC. Applications of dynamic contrastenhanced MRI in oncology drug development. In:Jackson A, Parker GJM, Buckley DL, editors. Dynamic contrastenhanced magnetic resonance imaging in oncology. Berlin: Springer-Verlag,2005:281-97.
[15]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[16]O'Connor JP, Jackson A, Parker GJ, et al.DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195
[17]Tropres I, Grimault S, Vaeth A, et al. Vessel size imaging. Magn Reson Med, 2001,45(3):397-408
[18]Jayson GC, Parker GJM, Mullamitha S, et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol,2005,23(5):973-981
[19]Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol,2006,24(5):769-777
[20]Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res,2005,11(8):2785-2808
[21]Wells P, West C, Jones T, et al. Measuring tumor pharmacodynamic response using PET proliferation probes:the case for 2-[(11)C]-thymidine. Biochim Biophy Acta,2004,1705(2):91-102
[22]Weber WA. Chaperoning drug development with PET. J Nucl Med,2006, 47(5):735-737
[23]Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol,2006,24(20):3282-3292
[24]Chenevert TL, Meyer CR, Moffat BA, et al. Diffusion MRI:a new strategy for assessment of cancer therapeutic efficacy. Mol Imaging,2002, 1(4):336-343
[25]Dzik-Jurasz A, Domenig C, George M, et al. Diffusion MRI for prediction of response of rectal cancer to chemoradiation. Lancet,2002,360(9329):307-308
[26]Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell,2007,11(1):83-95
[27]Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol,2003, 21(7):1404-1411
[28]World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva:World Health Organization,1979.
[29]Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst,2000,92(3):205-216
[30]US Food and Drug Administration. Guidance for industry:clinical trial endpoints for the approval of cancer drugs and biologics.2007. http://www.fda.gov/cder/guidance/7478fnl.pdf (accessed July 10,2008).
[31]Karrison TG, Maitland ML, Stadler WM, et al. Design of phase II cancer trials using a continuous endpoint of change in tumor size:application to a study of sorafenib and erlotinib in non-small-cell lung cancer. J Natl Cancer Inst,2007,99(19): 1455-1461
[32]Thomas AL, Morgan B, Horsfi eld MA, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol,2005,23(18): 4162-4171
[33]Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol,2007,25(13):1760-1764
[34]van Persijn van Meerten EL, Gelderblom H, et al. RECIST revised: implications for the radiologist. A review article on the modified RECIST guideline.Eur Radiol,2010,20(6):1456-1467
[35]Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol,2007,25(13): 1753-1759
[36]Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol,2007,25(21):3045-3054
[37]Partridge SC, Gibbs JE, Lu Y, et al. MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival. Am J Roentgenol,2005,184(6):1774-1781
[38]Booth CM, Calvert AH, Giaccone G, et al.Design and conduct of phase II studies of targeted anticancer therapy:Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer,2008,44(1):25-29
[39]Hong X, Choi H, Loyer EM, et al.Gastrointestinal stromal tumor:role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics,2006,26(2):481-495
[40]Choi H. Response evaluation of gastrointestinal stromal tumors. Oncologist, 2008,13 Suppl 2:4-7.
[41]Bulusu VR, Jephcott CR, et al. RECIST and Choi criteria for response assessment (RA) in patients with inoperable and metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate. Cambridge GIST study group experience. Proc Am Soc Clin Oncol,2007,25 (suppl 18):abstr 10019.
[42]Miles KA, Young H, Chica SL, et al. Quantitative contrastenhanced computed tomography:is there a need for system calibration? Eur Radiol,2007,17(4): 919-926
[43]Mullamitha SA, Ton NC, Parker GJ, et al. Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res,2007,13(7):2128-2135
[44]Clamp AR, O'Connor JP, Mitchell CL, et al. Pharmacodynamic assessment of the anti-angiogenic and anti-vascular properties of bevacizumab by magnetic resonance imaging in metastatic colorectal carcinoma (CRC). Proc Am Soc Clin Oncol,2008,26 (suppl 18):(abstr 3546)
[45]Kaiser WA, Zeitler E. MR imaging of the breast:fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology,1989,170 (3 Pt 1):681-686
[46]Gribbestad IS, Nilsen G, Fjosne HE, et al. Comparative signal intensity measurements in dynamic gadolinium-enhanced MR mammography. J Magn Reson Imaging,1994,4(3):477-480
[47]Lankester KJ, Maxwell RJ, Pedley RB, et al. Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody,131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J Oncol,2007,30(2):453-460
[48]Lankester KJ, Taylor JN, Stirling JJ, et al. Dynamic MRI for imaging tumor microvasculature:comparison of susceptibility and relaxivity techniques in pelvic tumors. J Magn Reson Imaging,2007,25(4):796-805
[49]LeachMO, Brindle KM, Evelhoch JL, et al. The assessment of antiangiogenic and anti-vascular therapies in early-stage clinical trials using magnetic resonance imaging:issues and recommendations. Br J Cancer,2005,92(9):1599-1610
[50]Ah-See ML, Makris A, Taylor NJ, et al. Early changes in functional dynamic magnetic resonance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res,2008,14(20):6580-6589
[51]Thukral A, Thomasson DM, Chow CK, et al. Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab-initial experience. Radiology,2007,244(3):727-735
[52]Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab,1983,3(1):1-7
[53]Kety SS. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev,1951,3(1):1-41
[54]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195.
[55]Tofts P, Brix G, Buckley D, et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer:standardized quantities and symbols. J Magn Reson Imaging,1999,10(3):223-232
[56]Johnson JA, Wilson TA. A model for capillary exchange. Am J Physiol, 1966,210(6):1299-1303
[57]St Lawrence KS, Lee TY. An adiabatic approximation to the tissue homogeneity model for water exchange in the brain:Ⅰ. Theoretical derivation. J Cereb Blood Flow Metab,1998,18(12):1365-1377
[58]Jackson A, O'Connor JP, Parker GJ, et al. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res,2007,13(12):3449-3459
[59]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer, 2007,96(2):189-195
[60]Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs:decorations or decision making tools? Eur J Nucl Med Mol Imaging.2010,37, Suppl 1:S164-182
[61]NCI, CIP, MR. Workshop on translational research in cancer: recommendations for MR measurement methods at 1-5-Tesla and endpoints for use in phase 1/2a trials of anti-cancer therapeutics affecting tumor vascular function. http://imaging.cancer.gov/reportsandpublications/ReportsandPresentations/Magnetic Resonance (accessed Dec 11,2006).
[62]Conrad C, Friedman H, Reardon D, et al. A phase Ⅰ/Ⅱ trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol (Meeting Abstracts),2004. Vol.22.
[63]Flaherty KT, Rosen MA, Heitjan DF, et al. Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther,2008,7(4):496-501
[64]Nagashima T, Sakakibara M, Miyazaki M, et al.Dynamic enhanced MRI and chemosensitivity in breast cancer. Nippon Rinsho,2007,28,65 Suppl 6:530-534
[65]Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol,2006,24(5):769-777
[66]Galbraith SM, Rustin GJ, LodgeMA, et al. Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol,2002,20(18): 3826-3840
[67]Cheng HL. Dynamic contrast-enhanced MRI in oncology drug development. Curr Clin Pharmacol,2007,2(2):111-122
[68]Mross K, Fasol U, Frost A, et al. DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases:a randomized phase I study. J Angiogenes Res,2009,21,1:5
[69]Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol,2007,25(21):3045-3054
[70]Keunen O, Johansson M, Oudin A, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A, 2011,108(9):3749-3754
[71]Koehne C, Bajetta E, Lin E, et al. Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2). Proc Am Soc Clin Oncol, 2006,24 (suppl 18):(abstr 3508)
[72]Hillman GG, Singh-Gupta V, Al-Bashir AK, et al. Dynamic contrast-enhanced magnetic resonance imaging of sunitinib-induced vascular changes to schedule chemotherapy in renal cell carcinoma xenograft tumors.Transl Oncol, 2010,3(5):293-306.
[73]Jackson A. Analysis of dynamic contrast enhanced MRI. Br J Radiol,2004, 77(2):S154-66.
[74]Robinson SP, McIntyre DJ, Checkley D, et al. Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging. Br J Cancer, 2003,88(10):1592-1597
[75]McPhail LD, Griffi ths JR, Robinson SP. Assessment of tumor response to the vascular disrupting agents 5,6-dimethylxanthenone-4-acetic Acid or combretastatin-4-phosphate by intrinsic susceptibility magnetic resonance imaging. Int J Radiat Oncol Biol Phys,2007,69(4):1238-1245
[76]Donahue KM, Krouwer HG, Rand SD, et al. Utility of simultaneously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients. Magn Reson Med,2000,43(6):845-853
[77]Seddon BM, Payne GS, Simmons L, et al. Phase I pharmacokinetic and magnetic resonance spectroscopic study of the non-invasive hypoxia probe SR-4554. Proc Am Soc Clin Oncol,2002,21:91b.
[78]Hunjan S, Zhao D, Constantinescu A, et al. Tumour oximetry:demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning Prostate R3327-AT1 rat tumour. Int J Radiat Oncol Biol Phys,2001,49(4):1097-1108
[79]Zhao D, Constantinescu A, Hahn EW, et al. Tumour oxygen dynamics with respect to growth and respiratory challenge:investigation of the Dunning Prostate R3326-HI tumour. Radiat Res,2001,156(5 Pt 1):510-520
[80]McSheehy PM, Leach MO, Judson IR, et al. Metabolites of 29-fluoro-29-deoxy-D-glucose detected by 19F magnetic resonance spectroscopy in vivo predict response of murine RIF-1 tumors to 5-fluorouracil. Cancer Res,2000,60(8): 2122-2127.
[81]Patterson DM, Padhani AR, Collins DJ. Technology insight:water diffusion MRI-a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol, 2008,5(4):220-233
[82]Gerstner ER, Duda DG, di Tomaso E, et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol,2009, 6(4):229-236
[83]Pickles MD, Gibbs P, Lowry M, et al. Diffusion changes precede size reduction in neoadjuvant treatment of breast cancer. Magn Reson Imaging,2006, 24(7):843-847
[84]Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A,2004, 101(36):13306-13311
[85]Ahn BC. Molecular Imaging for Drug Discovery and Development. Curr Pharm Biotechnol,2011 Feb 21. [Epub ahead of print]
[86]Rudin M, Weissleder R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov,2003,2(2):123-131
[87]Chen K, Conti PS. Target-specific delivery of peptide-based probes for PET imaging.Adv Drug Deliv Rev,2010,62(11):1005-1022
[88].Weissleder R, Ntziachristos V. Shedding light onto live molecular targets. Nat Med,2003,9(1):123-128
[89]Postema M, Gilja OH.Contrast-enhanced and targeted ultrasound. World J Gastroenterol,2011,17(1):28-41
[90]Deshpande N, Pysz MA, Willmann JK. Molecular ultrasound assessment of tumor angiogenesis. Angiogenesis.2010,13(2):175-188
[91]Kelloff GJ, Krohn KA, Larson SM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res,2005 11(22):7967-7985