非霍奇金淋巴瘤患者sVEGF、sbFGF水平变化及姜黄素对Raji细胞株VEGF表达影响的研究
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摘要
目的
研究非霍奇金淋巴瘤(non Hodgkin lymphoma,NHL)患者血清血管内皮生长因子(serum vascular endothelial growth factor,sVEGF)及血清碱性成纤维细胞生长因子(serum basic fibroblast growth factor,sbFGF)水平与临床特征的关系;探讨抗血管生成药物姜黄素对人非霍奇金淋巴瘤Raji细胞增殖及VEGF表达的影响,为临床抗血管新生治疗提供理论依据。
方法
ELISA法检测不同病期NHL患者sVEGF、sbFGF水平,并收集临床资料,进行统计分析;ELISA法检测姜黄素对Raji细胞上清中VEGF含量变化的影响;不同浓度姜黄素(5umol/L、10umol/L、25umol/L、50umol/L)作用于Raji细胞24h、48h、72h后,WST-1法检测姜黄素对细胞增殖的影响;倒置相差显微镜下观察Raji细胞形态及生长情况;Annexin-V/PI双标流式细胞术检测Raji细胞凋亡率。
结果
1. NHL患者sVEGF水平
(1)NHL初治化疗前36例,其sVEGF浓度为(443.59±203.48)pg/ml;正常对照组19例,其sVEGF浓度为(90.50±21.42)pg/ml,两组间差异有统计学意义(P<0.01)。
(2)化疗后完全缓解(complete remission,CR)者17例,其sVEGF浓度为(96.34±38.84)pg/ml;部分缓解(partial remission,PR)者11例,其sVEGF浓度为(109.54±46.37)pg/ml;复发进展(palindromia,PD)者8例,其sVEGF浓度为(553.96±250.08)pg/ml,初治化疗前sVEGF明显高于CR者(P<0.01)、也高于PR者(P<0.05);PD者sVEGF比初治化疗前稍高,但差异无统计学意义(P=0.526>0.05)。
(3)第一疗程达CR者9例,其化疗前sVEGF浓度为(152.11±57.98)pg/ml;未达CR者27例,其化疗前sVEGF浓度为(540.75±124.45)pg/ml,差异有统计学意义(P<0.05)。
(4)比较36例初治化疗前sVEGF与多个临床相关因素的关系,结果显示Ⅲ～Ⅳ期患者sVEGF水平高于Ⅰ～Ⅱ期者(P<0.05);高中危～高危组sVEGF水平高于低危～低中危组(P<0.05);LDH升高者sVEGF水平明显高于LDH正常者(P<0.05);β2-Mg升高者sVEGF水平明显高于β2-Mg正常者(P<0.05);而sVEGF水平与性别、年龄、全身症状及结外病变数目均无显著相关性(P均>0.05)。
2. NHL患者sbFGF水平
(1)NHL初治化疗前36例,其sbFGF浓度为(314.47±132.01)pg/ml;正常对照组19例,其sbFGF浓度为(78.55±36.35)pg/ml,两组间差异有统计学意义(P<0.05)。
(2)化疗后CR者17例,其sbFGF浓度为(82.28±34.85)pg/ml;PR者11例,其sbFGF浓度为(126.21±61.02)pg/ml;PD者8例,其sbFGF浓度为(338.40±161.12)pg/ml。初治者sbFGF浓度明显高于CR、PR者(P均<0.05);PD者sbFGF浓度比初治化疗前稍高,但差异无统计学意义(P=0.246>0.05)。
(3)第一疗程达CR者9例,其化疗前sbFGF浓度为(151.14±35.09)pg/ml;未能达CR者27例,其化疗前sbFGF浓度为(346.39±121.40)pg/ml,差异有统计学意义(P<0.05)。
(4)比较36例初治患者sbFGF与多个临床相关因素的关系,结果显示Ⅲ～Ⅳ期患者sbFGF水平高于Ⅰ～Ⅱ期者(P<0.05);高中危～高危组sbFGF水平高于低危～低中危组(P<0.05);LDH升高者sbFGF水平明显高于LDH正常者(P<0.05);β2-Mg升高者sbFGF水平明显高于β2-Mg正常者(P<0.05);而sbFGF水平与性别、年龄、全身症状及结外病变数目均无显著相关性(P均>0.05)。
3. sVEGF与sbFGF的相关性
pearson相关分析表明sVEGF与sbFGF具有显著正相关性(r=0.548,P<0.05)。
4.姜黄素对Raji细胞上清VEGF含量的影响
ELISA法检测10、25umol/L姜黄素对Raji细胞作用24h后上清液中VEGF含量的变化,结果显示,对照组上清液中VEGF浓度为(707.92±55.92)pg/ml;而10、25umol/L姜黄素处理组细胞上清液中VEGF浓度分别为(369.73±14.22)pg/ml、(178.24±21.18)pg/ml,与对照组相比两者均显著性降低(P均<0.05)。
5.姜黄素处理Raji细胞后WST-1法检测结果
5umol/L姜黄素对Raji细胞无明显抑制作用;10μmol/L、25μmol/L、50μmol/L姜黄素对Raji细胞增殖有显著抑制作用,呈浓度和时间依赖性。
6.姜黄素处理Raji细胞后形态变化
倒置相差显微镜下可见Raji细胞由成团生长变为单个散在,细胞数明显减少,细胞体积变小,折光性减弱,有的细胞膜破裂,可见细胞碎片。
7.姜黄素对Raji细胞凋亡的影响
流式细胞仪检测浓度为10、25umol/L姜黄素对Raji细胞凋亡的影响,结果示随着姜黄素作用浓度及时间增加,细胞凋亡率随之增加。作用24h,Raji细胞凋亡率分别为11.12%、25.07%;作用48h,凋亡率分别为14.74%、33.50%;作用72h,凋亡率分别为25.11%、55.98%,均高于对照组1.75%、2.25%、2.77%的凋亡率(P均<0.01)。
结论
1. NHL患者sVEGF、sbFGF水平显著高于正常对照,并与临床分期、IPI预后分组、LDH及β2-Mg有关。提示NHL的发病与血管新生有关,且可联合其他指标一起作为病情监测、预后评估的指标。
2.姜黄素能够抑制Raji细胞分泌VEGF,其抑制作用存在浓度依赖性。提示姜黄素具有抑制血管新生的作用,通过其作用达到抗NHL的目的,且为其他抗血管新生药物应用于NHL治疗提供参考。
3.姜黄素在一定浓度范围内可以明显抑制Raji细胞增殖,诱导Raji细胞凋亡,并呈浓度和时间依赖性。说明抑制血管新生有可能达到诱导Raji细胞凋亡的作用。
Objective
This study focused on the expression level of serum vascular endothelial growth factor(sVEGF) and serum basic fibroblast growth factor(sbFGF) in non Hodgkin lymphoma(NHL) patients and the relationship between them and clinical features; approach the affects of curcumin on proliferation and VEGFs′expression in Raji cells. The study provides a theory evidence for therapy of anti-vessel neogenesis in clinic.
Methods
We measured the sVEGF and sbFGF in NHL patients by ELISA, and collect clinical materials and analyze the data with SPSS. After Raji cells were treated with curcumin at different concentrations(5umol/L,10umol/L,25umol/L,50umol/L) and different time (24h, 48h,72h), cell proliferation was tested by WST-1 assay; the morphological changes of cells were observed by inverted phase contrast microscope; the apoptosis of Raji cells was studied by Annexin V/PI double-labeled flow cytometry; the change of VEGF contents in cultured supernatants of Raji cells treated with different concentratins of curcumin were measured by ELISA.
Results
1. The sVEGF levels in NHL patients
(1) The sVEGF levels in untreated 36 NHL patients is 443.59±203.48pg/ml, significantly higher than that of healthy controls(90.50±21.42pg/ml)(P<0.01).
(2) The sVEGF levels in 17 complete remission(CR) patients is 96.34±38.84pg/ml, 11 partial remission(PR) patients is 109.54±46.37pg/ml, and 8 palindromia(PD) patients is 553.96±250.08pg/ml. The sVEGF levels of untreated NHL patients was significantly higher than that of patients in CR (P<0.01), and was also higher than that of patients in PR(P<0.05); the sVEGF levels with PD was significantly higher than that of healthy controls(P<0.01), and was also higher than that of untreated patients, but no significance between them(P=0.526).
(3) The sVEGF levels in 9 CR patients in the first cycle chemotherapy is 152.11±57.98 pg/ml, significantly lower than the sVEGF levels in 27 not CR patients in the first cycle chemotherapy (540.75±124.45 pg/ml)( P<0.05).
(4) The sVEGF levels in NHL patients with advanced Ann Arbor stage(P<0.05)、high IPI scores(P<0.05) were significantly higher. Compared with those with normal LDH levels, sVEGF levels in NHL patients with higher LDH were elevated(P<0.05); Compared with those with normalβ2-Mg levels, sVEGF levels inβ2-Mg patients with higherβ2-Mg were elevated(P<0.05). But there were no difference about sVEGF levels in untreated NHL patients with different gender, age, B symptoms and number of extranodal site involved(P>0.05).
2. The sbFGF levels in NHL patients
(1) The sbFGF levels in untreated 36 NHL patients is 314.47±132.01pg/ml, significantly higher than that of healthy controls(78.55±36.35pg/ml) (P<0.05).
(2) The sbFGF levels in 17 CR patients is 82.28±34.85pg/ml, in 11 PR patients is 126.21±61.02pg/ml, and in 8 PD patients is 338.40±161.12pg/ml. The sbFGF levels of untreated NHL patients was significantly higher than that of patients in CR and in PR(P<0.05); the sbFGF levels with PD was significantly higher than that of healthy controls(P<0.01), and was also higher than that of untreated patients, but no significance between them(P=0.246).
(3) The sbFGF levels in 9 CR patients in the first cycle chemotherapy is 151.14±35.09 pg/ml, significantly lower than the sbFGF levels in 27 not CR patients in the first cycle chemotherapy (346.39±121.40pg/ml)( P<0.05).
(4) The sbFGF levels in NHL patients with advanced Ann Arbor stage(P<0.05)、high IPI scores(P<0.05) were significantly higher. Compared with those with normal LDH levels, sbFGF levels in NHL patients with higher LDH were elevated(P<0.05); Compared with those with normalβ2-Mg levels, sbFGF levels inβ2-Mg patients with higherβ2-Mg were elevated(P<0.05). But there were no difference about sbFGF levels in untreated NHL patients with different gender, age, B symptoms and number of extranodal site involved(P>0.05).
3. The correlation between sVEGF and sbFGF
There is positive correlation between sVEGF level and sbFGF level in NHL patients(r=0.548,P<0.05).
4. The change of VEGF contents in cultured supernatants of Raji cells
The change of VEGF contents in cultured supernatants of Raji cells treated with different concentratins of curcumin(10μmol/L, 25μmol/L) were measured by ELISA, the levels of VEGF were 369.73±14.22pg/ml, 178.24±21.18pg/ml, and significantly lower than that of the control group′s (707.92±55.92pg/ml).
5. The results of WST-1
There was no obviously refrain proliferation of Raji cells in 5umol/L curcumin; but in certain range of concentration (10μmol/L, 25μmol/L, 50μmol/L ), curcumin could obviously refrain proliferation of Raji cells in a dose and time dependent manner.
6. The morphological changes of Raji cells
The morphological changes of cells were observed by inverted phase contrast microscope, we can found that the Raji cells turned into disorder from conglobation, the cell population obviously was decreased and the cell volume shrinked, the refraction weakened, the cell membrance disrupted, and we can see cell debris.
7. The apoptosis of Raji cells
Through flow cytometry, we can found that the apoptosis rate of Raji cells was increased as the concentration of curcumin and action time were increased.
Conclusions
1. Serum VEGF、bFGF levels of NHL patients were higher than that of healthy adults, and were associated with advanced Ann Arbor stage, high IPI scores, LDH, andβ2-Mg. Angiogenesis perhaps involved in the development of NHL, and might be used to monitor patients conditions、evaluate prognosis with other indexes.
2. Curcumin can inhibit VEGF secretion of Raji cells , its relied on concentrations. These results suggest that curcumin can anti-vessel neogenesis.
3. Curcumin can significantly inhibit Raji cells proliferation in certain range of concentration, its relied on concentrations and times.
研究非霍奇金淋巴瘤(non Hodgkin lymphoma,NHL)患者血清血管内皮生长因子(serum vascular endothelial growth factor,sVEGF)及血清碱性成纤维细胞生长因子(serum basic fibroblast growth factor,sbFGF)水平与临床特征的关系;探讨抗血管生成药物姜黄素对人非霍奇金淋巴瘤Raji细胞增殖及VEGF表达的影响,为临床抗血管新生治疗提供理论依据。
方法
ELISA法检测不同病期NHL患者sVEGF、sbFGF水平,并收集临床资料,进行统计分析;ELISA法检测姜黄素对Raji细胞上清中VEGF含量变化的影响;不同浓度姜黄素(5umol/L、10umol/L、25umol/L、50umol/L)作用于Raji细胞24h、48h、72h后,WST-1法检测姜黄素对细胞增殖的影响;倒置相差显微镜下观察Raji细胞形态及生长情况;Annexin-V/PI双标流式细胞术检测Raji细胞凋亡率。
结果
1. NHL患者sVEGF水平
(1)NHL初治化疗前36例,其sVEGF浓度为(443.59±203.48)pg/ml;正常对照组19例,其sVEGF浓度为(90.50±21.42)pg/ml,两组间差异有统计学意义(P<0.01)。
(2)化疗后完全缓解(complete remission,CR)者17例,其sVEGF浓度为(96.34±38.84)pg/ml;部分缓解(partial remission,PR)者11例,其sVEGF浓度为(109.54±46.37)pg/ml;复发进展(palindromia,PD)者8例,其sVEGF浓度为(553.96±250.08)pg/ml,初治化疗前sVEGF明显高于CR者(P<0.01)、也高于PR者(P<0.05);PD者sVEGF比初治化疗前稍高,但差异无统计学意义(P=0.526>0.05)。
(3)第一疗程达CR者9例,其化疗前sVEGF浓度为(152.11±57.98)pg/ml;未达CR者27例,其化疗前sVEGF浓度为(540.75±124.45)pg/ml,差异有统计学意义(P<0.05)。
(4)比较36例初治化疗前sVEGF与多个临床相关因素的关系,结果显示Ⅲ～Ⅳ期患者sVEGF水平高于Ⅰ～Ⅱ期者(P<0.05);高中危～高危组sVEGF水平高于低危～低中危组(P<0.05);LDH升高者sVEGF水平明显高于LDH正常者(P<0.05);β2-Mg升高者sVEGF水平明显高于β2-Mg正常者(P<0.05);而sVEGF水平与性别、年龄、全身症状及结外病变数目均无显著相关性(P均>0.05)。
2. NHL患者sbFGF水平
(1)NHL初治化疗前36例,其sbFGF浓度为(314.47±132.01)pg/ml;正常对照组19例,其sbFGF浓度为(78.55±36.35)pg/ml,两组间差异有统计学意义(P<0.05)。
(2)化疗后CR者17例,其sbFGF浓度为(82.28±34.85)pg/ml;PR者11例,其sbFGF浓度为(126.21±61.02)pg/ml;PD者8例,其sbFGF浓度为(338.40±161.12)pg/ml。初治者sbFGF浓度明显高于CR、PR者(P均<0.05);PD者sbFGF浓度比初治化疗前稍高,但差异无统计学意义(P=0.246>0.05)。
(3)第一疗程达CR者9例,其化疗前sbFGF浓度为(151.14±35.09)pg/ml;未能达CR者27例,其化疗前sbFGF浓度为(346.39±121.40)pg/ml,差异有统计学意义(P<0.05)。
(4)比较36例初治患者sbFGF与多个临床相关因素的关系,结果显示Ⅲ～Ⅳ期患者sbFGF水平高于Ⅰ～Ⅱ期者(P<0.05);高中危～高危组sbFGF水平高于低危～低中危组(P<0.05);LDH升高者sbFGF水平明显高于LDH正常者(P<0.05);β2-Mg升高者sbFGF水平明显高于β2-Mg正常者(P<0.05);而sbFGF水平与性别、年龄、全身症状及结外病变数目均无显著相关性(P均>0.05)。
3. sVEGF与sbFGF的相关性
pearson相关分析表明sVEGF与sbFGF具有显著正相关性(r=0.548,P<0.05)。
4.姜黄素对Raji细胞上清VEGF含量的影响
ELISA法检测10、25umol/L姜黄素对Raji细胞作用24h后上清液中VEGF含量的变化,结果显示,对照组上清液中VEGF浓度为(707.92±55.92)pg/ml;而10、25umol/L姜黄素处理组细胞上清液中VEGF浓度分别为(369.73±14.22)pg/ml、(178.24±21.18)pg/ml,与对照组相比两者均显著性降低(P均<0.05)。
5.姜黄素处理Raji细胞后WST-1法检测结果
5umol/L姜黄素对Raji细胞无明显抑制作用;10μmol/L、25μmol/L、50μmol/L姜黄素对Raji细胞增殖有显著抑制作用,呈浓度和时间依赖性。
6.姜黄素处理Raji细胞后形态变化
倒置相差显微镜下可见Raji细胞由成团生长变为单个散在,细胞数明显减少,细胞体积变小,折光性减弱,有的细胞膜破裂,可见细胞碎片。
7.姜黄素对Raji细胞凋亡的影响
流式细胞仪检测浓度为10、25umol/L姜黄素对Raji细胞凋亡的影响,结果示随着姜黄素作用浓度及时间增加,细胞凋亡率随之增加。作用24h,Raji细胞凋亡率分别为11.12%、25.07%;作用48h,凋亡率分别为14.74%、33.50%;作用72h,凋亡率分别为25.11%、55.98%,均高于对照组1.75%、2.25%、2.77%的凋亡率(P均<0.01)。
结论
1. NHL患者sVEGF、sbFGF水平显著高于正常对照,并与临床分期、IPI预后分组、LDH及β2-Mg有关。提示NHL的发病与血管新生有关,且可联合其他指标一起作为病情监测、预后评估的指标。
2.姜黄素能够抑制Raji细胞分泌VEGF,其抑制作用存在浓度依赖性。提示姜黄素具有抑制血管新生的作用,通过其作用达到抗NHL的目的,且为其他抗血管新生药物应用于NHL治疗提供参考。
3.姜黄素在一定浓度范围内可以明显抑制Raji细胞增殖,诱导Raji细胞凋亡,并呈浓度和时间依赖性。说明抑制血管新生有可能达到诱导Raji细胞凋亡的作用。
Objective
This study focused on the expression level of serum vascular endothelial growth factor(sVEGF) and serum basic fibroblast growth factor(sbFGF) in non Hodgkin lymphoma(NHL) patients and the relationship between them and clinical features; approach the affects of curcumin on proliferation and VEGFs′expression in Raji cells. The study provides a theory evidence for therapy of anti-vessel neogenesis in clinic.
Methods
We measured the sVEGF and sbFGF in NHL patients by ELISA, and collect clinical materials and analyze the data with SPSS. After Raji cells were treated with curcumin at different concentrations(5umol/L,10umol/L,25umol/L,50umol/L) and different time (24h, 48h,72h), cell proliferation was tested by WST-1 assay; the morphological changes of cells were observed by inverted phase contrast microscope; the apoptosis of Raji cells was studied by Annexin V/PI double-labeled flow cytometry; the change of VEGF contents in cultured supernatants of Raji cells treated with different concentratins of curcumin were measured by ELISA.
Results
1. The sVEGF levels in NHL patients
(1) The sVEGF levels in untreated 36 NHL patients is 443.59±203.48pg/ml, significantly higher than that of healthy controls(90.50±21.42pg/ml)(P<0.01).
(2) The sVEGF levels in 17 complete remission(CR) patients is 96.34±38.84pg/ml, 11 partial remission(PR) patients is 109.54±46.37pg/ml, and 8 palindromia(PD) patients is 553.96±250.08pg/ml. The sVEGF levels of untreated NHL patients was significantly higher than that of patients in CR (P<0.01), and was also higher than that of patients in PR(P<0.05); the sVEGF levels with PD was significantly higher than that of healthy controls(P<0.01), and was also higher than that of untreated patients, but no significance between them(P=0.526).
(3) The sVEGF levels in 9 CR patients in the first cycle chemotherapy is 152.11±57.98 pg/ml, significantly lower than the sVEGF levels in 27 not CR patients in the first cycle chemotherapy (540.75±124.45 pg/ml)( P<0.05).
(4) The sVEGF levels in NHL patients with advanced Ann Arbor stage(P<0.05)、high IPI scores(P<0.05) were significantly higher. Compared with those with normal LDH levels, sVEGF levels in NHL patients with higher LDH were elevated(P<0.05); Compared with those with normalβ2-Mg levels, sVEGF levels inβ2-Mg patients with higherβ2-Mg were elevated(P<0.05). But there were no difference about sVEGF levels in untreated NHL patients with different gender, age, B symptoms and number of extranodal site involved(P>0.05).
2. The sbFGF levels in NHL patients
(1) The sbFGF levels in untreated 36 NHL patients is 314.47±132.01pg/ml, significantly higher than that of healthy controls(78.55±36.35pg/ml) (P<0.05).
(2) The sbFGF levels in 17 CR patients is 82.28±34.85pg/ml, in 11 PR patients is 126.21±61.02pg/ml, and in 8 PD patients is 338.40±161.12pg/ml. The sbFGF levels of untreated NHL patients was significantly higher than that of patients in CR and in PR(P<0.05); the sbFGF levels with PD was significantly higher than that of healthy controls(P<0.01), and was also higher than that of untreated patients, but no significance between them(P=0.246).
(3) The sbFGF levels in 9 CR patients in the first cycle chemotherapy is 151.14±35.09 pg/ml, significantly lower than the sbFGF levels in 27 not CR patients in the first cycle chemotherapy (346.39±121.40pg/ml)( P<0.05).
(4) The sbFGF levels in NHL patients with advanced Ann Arbor stage(P<0.05)、high IPI scores(P<0.05) were significantly higher. Compared with those with normal LDH levels, sbFGF levels in NHL patients with higher LDH were elevated(P<0.05); Compared with those with normalβ2-Mg levels, sbFGF levels inβ2-Mg patients with higherβ2-Mg were elevated(P<0.05). But there were no difference about sbFGF levels in untreated NHL patients with different gender, age, B symptoms and number of extranodal site involved(P>0.05).
3. The correlation between sVEGF and sbFGF
There is positive correlation between sVEGF level and sbFGF level in NHL patients(r=0.548,P<0.05).
4. The change of VEGF contents in cultured supernatants of Raji cells
The change of VEGF contents in cultured supernatants of Raji cells treated with different concentratins of curcumin(10μmol/L, 25μmol/L) were measured by ELISA, the levels of VEGF were 369.73±14.22pg/ml, 178.24±21.18pg/ml, and significantly lower than that of the control group′s (707.92±55.92pg/ml).
5. The results of WST-1
There was no obviously refrain proliferation of Raji cells in 5umol/L curcumin; but in certain range of concentration (10μmol/L, 25μmol/L, 50μmol/L ), curcumin could obviously refrain proliferation of Raji cells in a dose and time dependent manner.
6. The morphological changes of Raji cells
The morphological changes of cells were observed by inverted phase contrast microscope, we can found that the Raji cells turned into disorder from conglobation, the cell population obviously was decreased and the cell volume shrinked, the refraction weakened, the cell membrance disrupted, and we can see cell debris.
7. The apoptosis of Raji cells
Through flow cytometry, we can found that the apoptosis rate of Raji cells was increased as the concentration of curcumin and action time were increased.
Conclusions
1. Serum VEGF、bFGF levels of NHL patients were higher than that of healthy adults, and were associated with advanced Ann Arbor stage, high IPI scores, LDH, andβ2-Mg. Angiogenesis perhaps involved in the development of NHL, and might be used to monitor patients conditions、evaluate prognosis with other indexes.
2. Curcumin can inhibit VEGF secretion of Raji cells , its relied on concentrations. These results suggest that curcumin can anti-vessel neogenesis.
3. Curcumin can significantly inhibit Raji cells proliferation in certain range of concentration, its relied on concentrations and times.
引文
[1]沈志祥,朱雄增主编.恶性淋巴瘤[M].第1版,北京:人民卫生出版社,2003:序言.
[2] FolkmanJ,ShingY.Angiogenesis[J].J Biol Chem,1992,267(16):10931-10934.
[3] Hahm ER,Gho YS,Park S,et al.Synthetic curcumin analogs inhibit activator protein-1 transcription and tumor-induced angiogenesis. Biochem Biophys Res Commun, 2004,321(2):337-344.
[4] Gururaj AE,Belkavadi M,Venkatesh D,et al. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun,2002,297:934-942.
[5] Brattstrom D,Bergqvist P,Hesselius A,et al.Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumors and poorer survival in non-small cell lung cancer patients.Lung Cancer,2002,37:57-63.
[6]汪伟,丁强,张元芳等.膀胱肿瘤手术前后血清和尿液bFGF浓度监测的临床意义[J].中华泌尿外科杂志,2004,25(4):276.
[7]张之南主编.血液病诊断及疗效标准[M].第2版,北京:科学出版社,1998:349-358.
[8] Weryńska B.VEGF in the cancer anorexia-cachexia syndrome in patients with lung cancer.Pneumonol Alergol Pol,2006,74(2):186-90.
[9] Kiselyov A,Balakin KV,Tkachenko SE.VEGF/VEGFR signalling as a target for inhibiting angiogenesis [J].Expert Opin Investing Drugs,2007 Jan;16(1):83-107.
[10] Presta M,Dell’E ra P,Mitola S,et al.Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J].Cytokine Growth Factor Rev,2005,Apr; 16(2):159 -78.
[11] Wróbel T,Mazur G,Usnarska-Zubkiewicz L,et al.Vascular endothelial growth factor (VEGF)serum concentration in non-Hodgkin's lymphoma patients. Pol Arch Med Wewn,2004 Aug;112(2):919-923.
[12] Wróbel T,Poreba M,Mazur G,et al.Angiogenic and coagulation-fibrinolysis factors in non Hodgkin's lymphoma.Neoplasma,2006;53(3):253-258.
[13] Ribatti D,Vacca A,Nico B,et al.Angiogenesis spectrum in the stroma of B-cell non-Hodgkins lymphomas.An immuno-histochemical and ultrastructural study.Eur J Haematol,1996,56(1-2):45-53.
[14] StreubelB,Chott A,Huber D,et al.Lymphoma-specific genetic aberrations in-micro- vascular endothelial cells in B-cell lymphomas.N Engl J Med,2004,351(3): 250 -259.
[15] Lissoni P,Rovelli F,Malugani F,et al. Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer. Int J BiolMarkers,2003,18:152-155.
[16] Bertolini F,Paolucci M.Peccatori F.et al. Angiogenic growth factors and endostatin in non-hodgkin′s lymphoma. Br J Haematol,1999,106:504-509.
[17] Niitsu N,Okamoto M,Nakamine H,et al. Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin′s lymphoma. Eur J Haematol, 2002, 68:91-100.
[18] Hazar B,Paydas S,Zorludemir S,et al. Prognostic significance of microvessel density and vascular endothelial growth factor(VEGF) expression in non-Hodgkin′s lymphoma. Leuk Lymphoma,2003,44(12):2089-2093.
[19] Chiu TL,Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med,2009 Apr;23(4):469-75.
[20] IIbey YO,Ozbek E,Cekmen M,et al. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum Reprod,2009 Mar 11;8(1):2-10.
[21] Motterlini R,Foresti R,Bassi R,et al. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-I and protects endothelial cells against oxidative stress[J]. Free Radic Biol Med,2000,28(8):1303-1312.
[22] Aggarwal BB,Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol,2006,71(10):1397-1442.
[23] Duvoix A,Blasius R,Delhalle S,et al. Chemopreventive and therapeutic effects of curcumin. Cancer Lett,2005,223(2):181-190.
[24]孙春艳,刘新月,陈燕.姜黄素抗肿瘤机理研究新进展.国外医学肿瘤学分册,2003,30(6):356-358.
[25]高承贤,丁志山,梁冰冰等.姜黄素对血管生成影响的实验研究[J].中药材,2003,26(7):499-502.
[26] Mitra A,Chakrabarit J,Banerji A,et al. Curcumin, a Potential Inhibitor of MMP-2 in Human Laryngeal Squamous Carcinoma Cells HEp2. J Environ Pathol Toxicol Oncol,2006,25(4):679-90.
[27] Kin MS,Kang HJ,Moon A. Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharm Res,2001,24(4):349-354.
[28] Gururaj AE,Belakavadi M,Venkatesh D,et al. Molecular mechanisms of anti- angiogenic effect of curcumin. Biochem Biophys Res Commun,2002,297:934-942.
[29] Arbiser JL,Klauber N,Rohan R,et al. Curcumin is an in vivo inhibitor of angio- genesis[J]. Mol Med,1998,4(6):376-383.
[30]杨和平,李剑明,唐春兰等.姜黄色素活性单体成分抗血管生成的实验研究.第三军医大学学报,2005,27(11):1068-1070.
[31]孙军,王贺玲,李岩.姜黄素对人肝癌细胞中血管内皮生长因子表达的影响.中华消化杂志,2006,26(12):843-844.
[32] Bae MK,Kim SH,Jeong JW,et al. Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1[J]. Oncol Rep,2006,15(6):1557-1562.
[33] Kuo ML,Huang TS,Lin JK. Curcumin,an antioxidant and anti-tumor promoter,induced apoptosis in human leukemia cells[J]. Biochem Biophys Acta,1996,1317 (2):95-100.
[34] Han SS,Chung ST,Robertson DA,et al. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappaB, and p53[J]. Clin Immunol,1999,93(2):152-161.
[35] Jiang MC,Yang Yen HF,Yen JJ,et al. Curcumin induced apoptosis in immortalized NIH3T3 and malignant cancer cell lines[J]. Nutr Cancer,1996,26(1):111-120.
[1] Folkman J,ShingY. Angiogenesis[J].Jbiol Chem,1992,267(16):10931-10934.
[2] Perez-atayde AR,Sallan SE,Te drow U,et al. Spectrum of tumor angiogenisis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol,1997,150:815-821.
[3]陈川,俞德超,滕理送.以VEGF/VEGFR为靶点的抗肿瘤药物的研究进展.中国肿瘤生物治疗杂志,2007 5;14(3):291-295.
[4]沈彬,裴福兴.碱性成纤维细胞生长因子缓释微球促周围神经再生作用的研究进展.中华创伤杂志,2005,21(3):233-236.
[5] Okada-Ban M,Thiery JP,Jouanneau J,et al. Fibroblast growth factor-2[J].Int J Biochem,-2000,32(3):263-267.
[6] Jungnickel J,Claus P,Gransalke K,et al.Targeted disruption of the FGF-2 gene affects the response to peripheral nerve injury.Mol Cell Neurosci,2004,25:444-452.
[7]于德新,王滨.血管生长因子与肝细胞性肝癌的关系.肿瘤防治杂志,2004,11(3):331-334.
[8] Kiselyov A,Balakin KV,Tkachenko SE.VEGF/VEGFR signalling as a target for inhibiting angiogenesis [J].Expert Opin Investing Drugs,2007 Jan;16(1):83-107.
[9] Presta M ,Dell’E ra P,Mitola S,et al.Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J].Cytokine Growth Factor Rev,2005,Apr; 16(2):159- 178.
[10] West A F,O,Donnell M,CharltonR G,et al.Correlation of vascular endothelial growth factor expression with fibroblast growth factor-2 expression and clinicopathologic parameters in human prostate cancer[J].Br J Cancer,2001,85(4):576-583.
[11] Yoshiji H,Kuriyama S,Yoshii J,et al.Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma [J]. Hepatology,2002,35(4):834-842.
[12] Giles FJ,Vose JM,Do KA.Clinical relevance of circulating angiogenic factors in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma. Leuk Res,2004 Jun;-28(6):595-604.
[13] Wróbel T,Mazur G,Usnarska-Zubkiewicz L,et al.Vascular endothelial growth factor (VEGF) serum concentration in non-Hodgkin's lymphoma patients. Pol Arch Med Wewn,2004 Aug;112(2):919-923.
[14] Salven P,Teerenhovi L,Joensuu H.A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin's lymphoma.Blood,1999 Nov 15;94(10):3334-3339.
[15] Xia Y,Sun XY,Zhang CQ,et al.Primary study of relationship between serum level of VEGF and non-Hodgkin's lymphoma in children and adolescent patients.Ai Zheng, 2004 Nov;23(11 Suppl):1448-1450.
[16] Passam FH,Sfiridaki A,Pappa C,et al.Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma;relation to clinical features and response to treatment. Int J Lab Hematol,2008 Feb;30(1):17-25.
[17] Ho CL,Sheu LF,Li CY.Immunohistochemical expression of angiogenic cytokines and their receptors in reactive benign lymph nodes and non-Hodgkin lymphoma. Ann Diagn Pathol,2003 Feb;7(1):1-8.
[18] Wróbel T,Poreba M,Mazur G,et al.Angiogenic and coagulation-fibrinolysis factors in non Hodgkin's lymphoma. Neoplasma,2006;53(3):253-258.
[19] Dong X,Han ZC,Yang R.Angiogenesis and antiangiogenic therapy in hematologic malignancies.Crit Rev Oncol Hematol,2007 May;62(2):105-118.
[20] J?rgensen JM,S?rensen FB,Bendix K,et al.Angiogenesis in non-Hodgkin's lymphoma clinico-pathological correlations and prognostic significance in specific subtypes. Leuk Lymphoma,2007 Mar;48(3):584-595.
[21] Pedersen LM,Klausen TW,Davidsen UH,et al.Early changes in serum IL-6 and VEGF levels predict clinical outcome following first-line therapy in aggressive non-Hodgkin's lymphoma.Ann Hematol,2005 Aug;84(8):510-516.
[22] Ho CL,Sheu LF,Li CY.Immunohistochemical expression of basic fibroblast growth factor, vascular endothelial growth factor, and their receptors in stage IV non-Hodgkin lymphoma.Appl Immunohistochem Mol Morphol,2002 Dec;10(4):316-321.
[23] Hazar B,Paydas S,Zorludemir S,et al.Prognostic significance of microvessel density and vascular endothelial growth factor (VEGF) expression in non-Hodgkin's lymphoma.Leuk Lymphoma,2003 Dec;44(12):2089-2093.
[24] Giles FJ.The emerging role of angiogenesis inhibitors in hematologic malignancies. Oncology(Williston Park),2002 May;16(5 Suppl 4);23-29.
[25]翟鑫,王玉亚,宫平.以血管内皮生长因子及其受体为靶点的肿瘤血管生成抑制剂的研究进展.中国药物化学杂志,2006 2;16(1):60-64.
[26]高斌斌,徐忠法.抗肿瘤血管生成及其联合放化疗的研究进展.中华肿瘤防治杂志,2006,13(3):235-238.
[27] Ferrara N,Hillan KJ,Gerber HP,et al.Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer [J].Nat Rev Drug Discov,2004,3(5):391-400.
[28] Konner J,Dupont J.Use of soluble recombinant decoy receptor vascular endothelial growth factor trap(VEGF Trap) to inhibit vascular endothelial growth factor activity [J].Clin Colorectal Cancer,2004,4(Suppl,2):s813/s85.
[2] FolkmanJ,ShingY.Angiogenesis[J].J Biol Chem,1992,267(16):10931-10934.
[3] Hahm ER,Gho YS,Park S,et al.Synthetic curcumin analogs inhibit activator protein-1 transcription and tumor-induced angiogenesis. Biochem Biophys Res Commun, 2004,321(2):337-344.
[4] Gururaj AE,Belkavadi M,Venkatesh D,et al. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun,2002,297:934-942.
[5] Brattstrom D,Bergqvist P,Hesselius A,et al.Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumors and poorer survival in non-small cell lung cancer patients.Lung Cancer,2002,37:57-63.
[6]汪伟,丁强,张元芳等.膀胱肿瘤手术前后血清和尿液bFGF浓度监测的临床意义[J].中华泌尿外科杂志,2004,25(4):276.
[7]张之南主编.血液病诊断及疗效标准[M].第2版,北京:科学出版社,1998:349-358.
[8] Weryńska B.VEGF in the cancer anorexia-cachexia syndrome in patients with lung cancer.Pneumonol Alergol Pol,2006,74(2):186-90.
[9] Kiselyov A,Balakin KV,Tkachenko SE.VEGF/VEGFR signalling as a target for inhibiting angiogenesis [J].Expert Opin Investing Drugs,2007 Jan;16(1):83-107.
[10] Presta M,Dell’E ra P,Mitola S,et al.Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J].Cytokine Growth Factor Rev,2005,Apr; 16(2):159 -78.
[11] Wróbel T,Mazur G,Usnarska-Zubkiewicz L,et al.Vascular endothelial growth factor (VEGF)serum concentration in non-Hodgkin's lymphoma patients. Pol Arch Med Wewn,2004 Aug;112(2):919-923.
[12] Wróbel T,Poreba M,Mazur G,et al.Angiogenic and coagulation-fibrinolysis factors in non Hodgkin's lymphoma.Neoplasma,2006;53(3):253-258.
[13] Ribatti D,Vacca A,Nico B,et al.Angiogenesis spectrum in the stroma of B-cell non-Hodgkins lymphomas.An immuno-histochemical and ultrastructural study.Eur J Haematol,1996,56(1-2):45-53.
[14] StreubelB,Chott A,Huber D,et al.Lymphoma-specific genetic aberrations in-micro- vascular endothelial cells in B-cell lymphomas.N Engl J Med,2004,351(3): 250 -259.
[15] Lissoni P,Rovelli F,Malugani F,et al. Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer. Int J BiolMarkers,2003,18:152-155.
[16] Bertolini F,Paolucci M.Peccatori F.et al. Angiogenic growth factors and endostatin in non-hodgkin′s lymphoma. Br J Haematol,1999,106:504-509.
[17] Niitsu N,Okamoto M,Nakamine H,et al. Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin′s lymphoma. Eur J Haematol, 2002, 68:91-100.
[18] Hazar B,Paydas S,Zorludemir S,et al. Prognostic significance of microvessel density and vascular endothelial growth factor(VEGF) expression in non-Hodgkin′s lymphoma. Leuk Lymphoma,2003,44(12):2089-2093.
[19] Chiu TL,Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med,2009 Apr;23(4):469-75.
[20] IIbey YO,Ozbek E,Cekmen M,et al. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum Reprod,2009 Mar 11;8(1):2-10.
[21] Motterlini R,Foresti R,Bassi R,et al. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-I and protects endothelial cells against oxidative stress[J]. Free Radic Biol Med,2000,28(8):1303-1312.
[22] Aggarwal BB,Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol,2006,71(10):1397-1442.
[23] Duvoix A,Blasius R,Delhalle S,et al. Chemopreventive and therapeutic effects of curcumin. Cancer Lett,2005,223(2):181-190.
[24]孙春艳,刘新月,陈燕.姜黄素抗肿瘤机理研究新进展.国外医学肿瘤学分册,2003,30(6):356-358.
[25]高承贤,丁志山,梁冰冰等.姜黄素对血管生成影响的实验研究[J].中药材,2003,26(7):499-502.
[26] Mitra A,Chakrabarit J,Banerji A,et al. Curcumin, a Potential Inhibitor of MMP-2 in Human Laryngeal Squamous Carcinoma Cells HEp2. J Environ Pathol Toxicol Oncol,2006,25(4):679-90.
[27] Kin MS,Kang HJ,Moon A. Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharm Res,2001,24(4):349-354.
[28] Gururaj AE,Belakavadi M,Venkatesh D,et al. Molecular mechanisms of anti- angiogenic effect of curcumin. Biochem Biophys Res Commun,2002,297:934-942.
[29] Arbiser JL,Klauber N,Rohan R,et al. Curcumin is an in vivo inhibitor of angio- genesis[J]. Mol Med,1998,4(6):376-383.
[30]杨和平,李剑明,唐春兰等.姜黄色素活性单体成分抗血管生成的实验研究.第三军医大学学报,2005,27(11):1068-1070.
[31]孙军,王贺玲,李岩.姜黄素对人肝癌细胞中血管内皮生长因子表达的影响.中华消化杂志,2006,26(12):843-844.
[32] Bae MK,Kim SH,Jeong JW,et al. Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1[J]. Oncol Rep,2006,15(6):1557-1562.
[33] Kuo ML,Huang TS,Lin JK. Curcumin,an antioxidant and anti-tumor promoter,induced apoptosis in human leukemia cells[J]. Biochem Biophys Acta,1996,1317 (2):95-100.
[34] Han SS,Chung ST,Robertson DA,et al. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappaB, and p53[J]. Clin Immunol,1999,93(2):152-161.
[35] Jiang MC,Yang Yen HF,Yen JJ,et al. Curcumin induced apoptosis in immortalized NIH3T3 and malignant cancer cell lines[J]. Nutr Cancer,1996,26(1):111-120.
[1] Folkman J,ShingY. Angiogenesis[J].Jbiol Chem,1992,267(16):10931-10934.
[2] Perez-atayde AR,Sallan SE,Te drow U,et al. Spectrum of tumor angiogenisis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol,1997,150:815-821.
[3]陈川,俞德超,滕理送.以VEGF/VEGFR为靶点的抗肿瘤药物的研究进展.中国肿瘤生物治疗杂志,2007 5;14(3):291-295.
[4]沈彬,裴福兴.碱性成纤维细胞生长因子缓释微球促周围神经再生作用的研究进展.中华创伤杂志,2005,21(3):233-236.
[5] Okada-Ban M,Thiery JP,Jouanneau J,et al. Fibroblast growth factor-2[J].Int J Biochem,-2000,32(3):263-267.
[6] Jungnickel J,Claus P,Gransalke K,et al.Targeted disruption of the FGF-2 gene affects the response to peripheral nerve injury.Mol Cell Neurosci,2004,25:444-452.
[7]于德新,王滨.血管生长因子与肝细胞性肝癌的关系.肿瘤防治杂志,2004,11(3):331-334.
[8] Kiselyov A,Balakin KV,Tkachenko SE.VEGF/VEGFR signalling as a target for inhibiting angiogenesis [J].Expert Opin Investing Drugs,2007 Jan;16(1):83-107.
[9] Presta M ,Dell’E ra P,Mitola S,et al.Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis[J].Cytokine Growth Factor Rev,2005,Apr; 16(2):159- 178.
[10] West A F,O,Donnell M,CharltonR G,et al.Correlation of vascular endothelial growth factor expression with fibroblast growth factor-2 expression and clinicopathologic parameters in human prostate cancer[J].Br J Cancer,2001,85(4):576-583.
[11] Yoshiji H,Kuriyama S,Yoshii J,et al.Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma [J]. Hepatology,2002,35(4):834-842.
[12] Giles FJ,Vose JM,Do KA.Clinical relevance of circulating angiogenic factors in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma. Leuk Res,2004 Jun;-28(6):595-604.
[13] Wróbel T,Mazur G,Usnarska-Zubkiewicz L,et al.Vascular endothelial growth factor (VEGF) serum concentration in non-Hodgkin's lymphoma patients. Pol Arch Med Wewn,2004 Aug;112(2):919-923.
[14] Salven P,Teerenhovi L,Joensuu H.A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin's lymphoma.Blood,1999 Nov 15;94(10):3334-3339.
[15] Xia Y,Sun XY,Zhang CQ,et al.Primary study of relationship between serum level of VEGF and non-Hodgkin's lymphoma in children and adolescent patients.Ai Zheng, 2004 Nov;23(11 Suppl):1448-1450.
[16] Passam FH,Sfiridaki A,Pappa C,et al.Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma;relation to clinical features and response to treatment. Int J Lab Hematol,2008 Feb;30(1):17-25.
[17] Ho CL,Sheu LF,Li CY.Immunohistochemical expression of angiogenic cytokines and their receptors in reactive benign lymph nodes and non-Hodgkin lymphoma. Ann Diagn Pathol,2003 Feb;7(1):1-8.
[18] Wróbel T,Poreba M,Mazur G,et al.Angiogenic and coagulation-fibrinolysis factors in non Hodgkin's lymphoma. Neoplasma,2006;53(3):253-258.
[19] Dong X,Han ZC,Yang R.Angiogenesis and antiangiogenic therapy in hematologic malignancies.Crit Rev Oncol Hematol,2007 May;62(2):105-118.
[20] J?rgensen JM,S?rensen FB,Bendix K,et al.Angiogenesis in non-Hodgkin's lymphoma clinico-pathological correlations and prognostic significance in specific subtypes. Leuk Lymphoma,2007 Mar;48(3):584-595.
[21] Pedersen LM,Klausen TW,Davidsen UH,et al.Early changes in serum IL-6 and VEGF levels predict clinical outcome following first-line therapy in aggressive non-Hodgkin's lymphoma.Ann Hematol,2005 Aug;84(8):510-516.
[22] Ho CL,Sheu LF,Li CY.Immunohistochemical expression of basic fibroblast growth factor, vascular endothelial growth factor, and their receptors in stage IV non-Hodgkin lymphoma.Appl Immunohistochem Mol Morphol,2002 Dec;10(4):316-321.
[23] Hazar B,Paydas S,Zorludemir S,et al.Prognostic significance of microvessel density and vascular endothelial growth factor (VEGF) expression in non-Hodgkin's lymphoma.Leuk Lymphoma,2003 Dec;44(12):2089-2093.
[24] Giles FJ.The emerging role of angiogenesis inhibitors in hematologic malignancies. Oncology(Williston Park),2002 May;16(5 Suppl 4);23-29.
[25]翟鑫,王玉亚,宫平.以血管内皮生长因子及其受体为靶点的肿瘤血管生成抑制剂的研究进展.中国药物化学杂志,2006 2;16(1):60-64.
[26]高斌斌,徐忠法.抗肿瘤血管生成及其联合放化疗的研究进展.中华肿瘤防治杂志,2006,13(3):235-238.
[27] Ferrara N,Hillan KJ,Gerber HP,et al.Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer [J].Nat Rev Drug Discov,2004,3(5):391-400.
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