Objective This study aimed to investigate the effect of combretastatin A4 phosphate(CA4P)on proliferation,migration,and capillary tube formation of human umbilical vein endothelial cells(HUVECs)and the efficacy of tra...Objective This study aimed to investigate the effect of combretastatin A4 phosphate(CA4P)on proliferation,migration,and capillary tube formation of human umbilical vein endothelial cells(HUVECs)and the efficacy of transcatheter arterial embolization combined with CA4P in the treatment of rabbit VX2 liver tumor.Methods The effects of different concentrations of CA4P on proliferation,migration and capillary tube formation of HUVECs were investigated by cell proliferation assay,wound healing assay and capillary tube formation assay,respectively.Thirty-two rabbits implanted with liver VX2 tumors were randomly divided into 4 groups.After catheterization of the left hepatic artery,the infusion was performed using normal saline(group A),CA4P aqueous solution(group B),lipiodol and polyvinyl alcohol particles(group C),and CA4P lipiodol emulsion and polyvinyl alcohol particles(group D),respectively.Half of the animals in each group were euthanized for immunohistochemical analysis to evaluate microvessel density(MVD)at 3 days post-treatment.The other half were examined by MRI and histology to evaluate tumor growth and necrosis at 7 days post-treatment.Results CA4P could inhibit the proliferation,migration,and tube formation of HUVECs in cell experiments.After interventional treatment,the level of MVD in group D was lower than that in group C(P<0.01).The tumor volume in group C or D was lower than that in group A or B(P<0.01).The tumor necrosis rate was higher in group D than in the other groups.Conclusion The study suggests that CA4P could inhibit the proliferation,migration,and capillary tube formation of HUVECs,and transcatheter arterial embolization combined with CA4P could inhibit the growth of VX2 tumor and obviously induce tumor necrosis.展开更多
Combretastatin A4(CA4) possesses varying ability to cause vascular disruption in tumors,while the short half-life, low water solubility and deactivation of many CA4 analogs during storage limited its antitumor efficac...Combretastatin A4(CA4) possesses varying ability to cause vascular disruption in tumors,while the short half-life, low water solubility and deactivation of many CA4 analogs during storage limited its antitumor efficacy and drug stability. A novel macromolecular conjugate of CA4(CA4-PL) was synthesized by covalent bonding of CA4 onto poly(L-glutamic acid)-graft-polyethylene glycol(PLG-g-PEG) via Yamaguchi reaction. The obtained CA4-PL was characterized by ~1H NMR, GPC, and UV methods, and the properties of the nanoparticles composed of CA4-PL, including critical aggregation concentration, size and size distribution, and morphology, were investigated. CA4-PL can self-assemble to form micelle-like nanoparticles of 80～120 nm in diameter, which may have potential to improve the blood circulation period as well as the targetability of CA4, and find applications to treat various tumors when combined with traditional chemotherapy or radio therapy.展开更多
AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-i...AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-imaging(MRI), microangiography and histopathology.METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images(T2wI/T1wI) on a 3.0 T clinical MRIscanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced(DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg(treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg(control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve(AUC30). In vivo MRI findings were verified by postmortem techniques.RESULTS On CE-T1wIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure(66%) in R1-tumors at 1 h(P < 0.05), followed by further perfusion decrease at 12 h(P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors(92.6%) than in HCCs(50.2%)(P < 0.01); tumor vascularity heterogeneously scored +^+++ in HCCs but homogeneously scored ++ in R1-tumors.CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disruptingagents.展开更多
基金supported in part by the Fundamental Research Funds for the Central Universities(No.2042015kf0104)in part by the Hubei Provincial Natural Science Foundation of China(No.2015CFB343).
文摘Objective This study aimed to investigate the effect of combretastatin A4 phosphate(CA4P)on proliferation,migration,and capillary tube formation of human umbilical vein endothelial cells(HUVECs)and the efficacy of transcatheter arterial embolization combined with CA4P in the treatment of rabbit VX2 liver tumor.Methods The effects of different concentrations of CA4P on proliferation,migration and capillary tube formation of HUVECs were investigated by cell proliferation assay,wound healing assay and capillary tube formation assay,respectively.Thirty-two rabbits implanted with liver VX2 tumors were randomly divided into 4 groups.After catheterization of the left hepatic artery,the infusion was performed using normal saline(group A),CA4P aqueous solution(group B),lipiodol and polyvinyl alcohol particles(group C),and CA4P lipiodol emulsion and polyvinyl alcohol particles(group D),respectively.Half of the animals in each group were euthanized for immunohistochemical analysis to evaluate microvessel density(MVD)at 3 days post-treatment.The other half were examined by MRI and histology to evaluate tumor growth and necrosis at 7 days post-treatment.Results CA4P could inhibit the proliferation,migration,and tube formation of HUVECs in cell experiments.After interventional treatment,the level of MVD in group D was lower than that in group C(P<0.01).The tumor volume in group C or D was lower than that in group A or B(P<0.01).The tumor necrosis rate was higher in group D than in the other groups.Conclusion The study suggests that CA4P could inhibit the proliferation,migration,and capillary tube formation of HUVECs,and transcatheter arterial embolization combined with CA4P could inhibit the growth of VX2 tumor and obviously induce tumor necrosis.
基金supported by National Natural Science Foundation of China (No. 51373168)
文摘Combretastatin A4(CA4) possesses varying ability to cause vascular disruption in tumors,while the short half-life, low water solubility and deactivation of many CA4 analogs during storage limited its antitumor efficacy and drug stability. A novel macromolecular conjugate of CA4(CA4-PL) was synthesized by covalent bonding of CA4 onto poly(L-glutamic acid)-graft-polyethylene glycol(PLG-g-PEG) via Yamaguchi reaction. The obtained CA4-PL was characterized by ~1H NMR, GPC, and UV methods, and the properties of the nanoparticles composed of CA4-PL, including critical aggregation concentration, size and size distribution, and morphology, were investigated. CA4-PL can self-assemble to form micelle-like nanoparticles of 80～120 nm in diameter, which may have potential to improve the blood circulation period as well as the targetability of CA4, and find applications to treat various tumors when combined with traditional chemotherapy or radio therapy.
文摘AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate(CA4 P), among hepatocellular carcinomas(HCCs) and implanted rhabdomyosarcoma(R1) in the same rats by magneticresonance-imaging(MRI), microangiography and histopathology.METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images(T2wI/T1wI) on a 3.0 T clinical MRIscanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced(DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg(treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg(control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve(AUC30). In vivo MRI findings were verified by postmortem techniques.RESULTS On CE-T1wIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure(66%) in R1-tumors at 1 h(P < 0.05), followed by further perfusion decrease at 12 h(P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors(92.6%) than in HCCs(50.2%)(P < 0.01); tumor vascularity heterogeneously scored +^+++ in HCCs but homogeneously scored ++ in R1-tumors.CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disruptingagents.
