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Feng Chen - One of the best experts on this subject based on the ideXlab platform.
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Diverse responses to vascular disrupting agent Combretastatin A4 Phosphate: a comparative study in rats with hepatic and subcutaneous tumor allografts using MRI biomarkers, microangiography, and histopathology.
Translational oncology, 2013Co-Authors: Feng Chen, Marlein Miranda Cona, Yuanbo Feng, Jian Zhang, Alfons Verbruggen, Raymond OyenAbstract:OBJECTIVE: Differently located tumors of the same origin may exhibit diverse responses to the same therapeutics. To test this hypothesis, we compared the responses of rodent hepatic and subcutaneous engrafts of rhabdomyosarcoma-1 (R1) to a vascular disrupting agent Combretastatin A4 Phosphate (CA4P). METHODS: Twelve WAG/Rij rats, each bearing three R1 implanted in the right and left hepatic lobes and subcutaneously in the thoracic region, received CA4P intravenously at 5 mg/kg (n = 6) or solvent (n = 6). Therapeutic responses were compared interindividually and intraindividually among tumors of different sites till 48 hours after injection using in vivo MRI, postmortem digital microangiography, and histopathology. RESULTS: MRI revealed that the subcutaneous tumors (STs) significantly increased in volume than hepatic tumors (HTs) 48 hours after CA4P (P < .05). Relative to vehicle controls and treated group at baseline, necrosis ratio, apparent diffusion coefficient, and enhancement ratio changed slightly with the STs but significantly with HTs (P < .05) after CA4P treatment. Vessel density derived from microangiography was significantly lower in STs compared to HTs without CA4P treatment. CA4P treatment resulted in decreased vessel density in HTs, while it did not affect vessel density in STs. MRI and microangiography outcomes were supported by histopathologic findings. CONCLUSIONS: MRI and microangiography allowed quantitative comparison of therapeutic responses to CA4P in rats with multifocal tumors. The discovered diverse effects of the same drug on tumors of the same origin but different locations emphasize the presence of cancer heterogeneity and the importance of individualization of drug delivery.
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sequential systemic administrations of Combretastatin A4 Phosphate and radioiodinated hypericin exert synergistic targeted theranostic effects with prolonged survival on scid mice carrying bifocal tumor xenografts
Theranostics, 2013Co-Authors: Marlein Miranda Cona, Feng Chen, Yuanbo Feng, Lin Zhou, Guozhi Zhang, Johan Nuyts, Peter De Witte, Jian Zhang, Raymond Oyen, Alfons VerbruggenAbstract:Objectives: Based on the soil-to-seeds principle, we explored the small-molecular sequential dual-targeting theranostic strategy (SMSDTTS) for prolonged survival and imaging detectability in a xenograft tumor model. Materials and Methods: Thirty severe combined immunodeficiency (SCID) mice bearing bilateral radiation-induced fibrosarcoma-1 (RIF-1) subcutaneously were divided into group A of SMSDTTS with sequential intravenous injections of Combretastatin A4 Phosphate (CA4P) and 131I-iodohypericin (131I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of 131I-Hyp; and group C of vehicle control (10 mice per group). Tumoricidal events were monitored by in vivo magnetic resonance imaging (MRI) and planar gamma scintiscan, and validated by ex vivo autoradiography and histopathology. Besides, 9 mice received sequential intravenous injections of CA4P and 131I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h. Results: Gamma counting revealed fast clearance of 131I-Hyp from normal organs but intense accumulation in necrotic tumor over 120 h. After only one treatment, significantly prolonged survival (p<0.001) was found in group A compared to group B and C with median survival of 33, 22, and 21 days respectively. Tumor volume on day 15 was 2.0 ± 0.89, 5.66 ± 1.66, and 5.02 ± 1.0 cm3 with tumor doubling time 7.8 ± 2.8, 4.4 ± 0.67, and 4.5 ± 0.5 days respectively. SMSDTTS treated tumors were visualized as hot spots on gamma scintiscans, and necrosis over tumor ratio remained consistently high on MRI, autoradiography and histology. Conclusion: The synergistic antitumor effects, multifocal targetability, simultaneous theranostic property, and good tolerance of the SMSDTTS were evident in this experiment, which warrants further development for preclinical and clinical applications.
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diffusion weighted mr imaging allows monitoring the effect of Combretastatin A4 Phosphate on rabbit implanted vx2 tumor model 12 day dynamic results
European Journal of Radiology, 2012Co-Authors: Haibo Shao, Feng Chen, Jian Zhang, Xu Dai, Guoguang Fan, Ziping Sun, Hongxu ZhouAbstract:Abstract Objectives To investigate the 12-day dynamic characteristics of tumor response to intravenous administration of CA4P in rabbit VX2 tumor models. Methods Study protocol was approved by local ethical committee for animal care and use. Sixteen rabbits with 32 tumors on bilateral legs were randomly divided into treated and control groups. Conventional and DWI images were acquired before and 24 h, 4 days, 8 days and 12 days after treatment. The dynamic changes of tumor on images were correlated with histological results. ADCs were compared among and between groups at different time points. Results The tumors in treated group grew slower than those in control group. In treaded group, the mean ADC decreased slightly at 24 h point due to cell edema caused by ischemia. Then, it increased significantly at 4 days and 8 days because of progressive central necrosis. Finally, peripheral tumor proliferation caused a second decrease of ADC at 12 days. The significant difference of ΔADC% between the two groups at 24 h, 4 days and 8 days indicated that the change of ADC in treated group was really caused by CA4P. Conclusion The dynamic histological changes of tumor caused by CA4P as reflected exactly by diffusion-weighted MR imaging indicate a noninvasive measure for monitoring tumor vascular targeting treatment.
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treatment of rodent liver tumor with Combretastatin A4 Phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology
Investigative Radiology, 2009Co-Authors: Huaijun Wang, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Robert Hermans, Feng Chen, Jie Yu, Ronald R Peeters, Guy MarchalAbstract:Objectives:To document tumoricidal events after intravenous administration of a vascular targeting agent Combretastatin A-4-Phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.Materials and Methods:
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effect of vascular targeting agent in rat tumor model dynamic contrast enhanced versus diffusion weighted mr imaging
Radiology, 2005Co-Authors: Harriet C Thoeny, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Chris Boesch, Eric Verbeken, Guy Marchal, Robert Hermans, Feng Chen, Willy LanduytAbstract:PURPOSE: To compare dynamic contrast material–enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of Combretastatin A4 Phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADClow; b = 0, 50, and 100 sec/mm2) and high b gradient values (ADChigh; b = 500, 750, and 1000 sec/mm2). The difference between...
Guy Marchal - One of the best experts on this subject based on the ideXlab platform.
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treatment of rodent liver tumor with Combretastatin A4 Phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology
Investigative Radiology, 2009Co-Authors: Huaijun Wang, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Robert Hermans, Feng Chen, Jie Yu, Ronald R Peeters, Guy MarchalAbstract:Objectives:To document tumoricidal events after intravenous administration of a vascular targeting agent Combretastatin A-4-Phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.Materials and Methods:
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effect of vascular targeting agent in rat tumor model dynamic contrast enhanced versus diffusion weighted mr imaging
Radiology, 2005Co-Authors: Harriet C Thoeny, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Chris Boesch, Eric Verbeken, Guy Marchal, Robert Hermans, Feng Chen, Willy LanduytAbstract:PURPOSE: To compare dynamic contrast material–enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of Combretastatin A4 Phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADClow; b = 0, 50, and 100 sec/mm2) and high b gradient values (ADChigh; b = 500, 750, and 1000 sec/mm2). The difference between...
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diffusion weighted mr imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats
Radiology, 2005Co-Authors: Harriet C Thoeny, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Eric Verbeken, Guy Marchal, Feng Chen, Robert HermansAbstract:PURPOSE: To evaluate diffusion-weighted magnetic resonance (MR) imaging for monitoring tumor response in rats after administration of Combretastatin A4 Phosphate. MATERIALS AND METHODS: Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (Combretastatin A4 Phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for mult...
Willy Landuyt - One of the best experts on this subject based on the ideXlab platform.
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treatment of rodent liver tumor with Combretastatin A4 Phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology
Investigative Radiology, 2009Co-Authors: Huaijun Wang, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Robert Hermans, Feng Chen, Jie Yu, Ronald R Peeters, Guy MarchalAbstract:Objectives:To document tumoricidal events after intravenous administration of a vascular targeting agent Combretastatin A-4-Phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.Materials and Methods:
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effect of vascular targeting agent in rat tumor model dynamic contrast enhanced versus diffusion weighted mr imaging
Radiology, 2005Co-Authors: Harriet C Thoeny, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Chris Boesch, Eric Verbeken, Guy Marchal, Robert Hermans, Feng Chen, Willy LanduytAbstract:PURPOSE: To compare dynamic contrast material–enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of Combretastatin A4 Phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADClow; b = 0, 50, and 100 sec/mm2) and high b gradient values (ADChigh; b = 500, 750, and 1000 sec/mm2). The difference between...
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diffusion weighted mr imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats
Radiology, 2005Co-Authors: Harriet C Thoeny, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Eric Verbeken, Guy Marchal, Feng Chen, Robert HermansAbstract:PURPOSE: To evaluate diffusion-weighted magnetic resonance (MR) imaging for monitoring tumor response in rats after administration of Combretastatin A4 Phosphate. MATERIALS AND METHODS: Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (Combretastatin A4 Phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for mult...
Robert Hermans - One of the best experts on this subject based on the ideXlab platform.
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treatment of rodent liver tumor with Combretastatin A4 Phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology
Investigative Radiology, 2009Co-Authors: Huaijun Wang, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Robert Hermans, Feng Chen, Jie Yu, Ronald R Peeters, Guy MarchalAbstract:Objectives:To document tumoricidal events after intravenous administration of a vascular targeting agent Combretastatin A-4-Phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.Materials and Methods:
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effect of vascular targeting agent in rat tumor model dynamic contrast enhanced versus diffusion weighted mr imaging
Radiology, 2005Co-Authors: Harriet C Thoeny, Vincent Vandecaveye, Frederik De Keyzer, Hilde Bosmans, Chris Boesch, Eric Verbeken, Guy Marchal, Robert Hermans, Feng Chen, Willy LanduytAbstract:PURPOSE: To compare dynamic contrast material–enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of Combretastatin A4 Phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADClow; b = 0, 50, and 100 sec/mm2) and high b gradient values (ADChigh; b = 500, 750, and 1000 sec/mm2). The difference between...
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diffusion weighted mr imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats
Radiology, 2005Co-Authors: Harriet C Thoeny, Frederik De Keyzer, Hilde Bosmans, Willy Landuyt, Eric Verbeken, Guy Marchal, Feng Chen, Robert HermansAbstract:PURPOSE: To evaluate diffusion-weighted magnetic resonance (MR) imaging for monitoring tumor response in rats after administration of Combretastatin A4 Phosphate. MATERIALS AND METHODS: Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (Combretastatin A4 Phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for mult...
Gillian M. Tozer - One of the best experts on this subject based on the ideXlab platform.
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tie2 expressing macrophages limit the therapeutic efficacy of the vascular disrupting agent Combretastatin A4 Phosphate in mice
Journal of Clinical Investigation, 2011Co-Authors: Abigail F Welford, Daniela Biziato, Seth B Coffelt, Silvia Nucera, Matthew Fisher, Ferdinando Pucci, Clelia Di Serio, Luigi Naldini, Michele De Palma, Gillian M. TozerAbstract:Vascular-disrupting agents (VDAs) such as Combretastatin A4 Phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.
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Signaling interactions between RhoGTPase and cAMP/cGMP influence endothelial responses to the vascular disrupting agent Combretastatin A4 Phosphate
2010Co-Authors: Chryso Kanthou, Constantino Carlos Reyes-aldasoro, Gillian M. TozerAbstract:Background: Combretastatin A4 Phosphate (CA4P) is a tumour vascular disrupting agent (VDA) that targets endothelial microtubules, triggering remodelling of the actin cytoskeleton, contractility and disruption of VE-cadherin junctions through RhoGTPase/ROCK-dependent pathways. These events lead to a rise in endothelial monolayer permeability. A rise in permeability is considered crucial for vascular shutdown elicited by CA4P in vivo. CA4P also inhibits endothelial migration and induces mitotic arrest and apoptosis, so potentially it could also target tumour angiogenesis. Method: In this study, the nature of signalling interactions between Rho/ROCK and cAMP/cGMP and their influence on cytoskeletal and functional responses of endothelial cells to CA4P were investigated. Results: Several cAMP/cGMP analogues inhibited CA4P-induced Rho/ROCK activation and prevented actin remodeling, disruption of cell-to-cell junctions and permeability rise in endothelial monolayers. cAMP inhibits Rho by either protein kinase A (PKA)-dependent mechanisms or via activation of Epac1/Rap1. O-Me-cAMP, an analogue that selectively activates Epac1/Rap1 abolished activation of Rho/ROCK by CA4P while selective PKA activator 6-Bnz-cAMP only partially inhibited Rho/ROCK activation and actin remodelling by CA4P. Inhibitors of PKA did not alter endothelial responses to CA4P in the presence of cAMP analogues suggesting that cAMP acts primarily via Epac1/Rap1 to inhibit Rho/CA4P interactions. CA-4-P also inhibited endothelial migration and abolished lamellipodia at the leading edge of migrating cells in injured monolayers. Rho inhibitor C3 exoenzyme and ROCK inhibitor Y27632 as well as cAMP analogues re-established cell movement and formation of lamellipodia in wounded monolayers exposed to CA-4-P, suggesting that inhibitory effects on migration were mediated via Rho/ROCK. Conclusion: Deciphering molecular pathways that modulate endothelial responses to VDAs is important for further targeting. Our data demonstrate that interactions between cGMP/cAMP and Rho influence both the vascular disrupting and anti-angiogenic activities of CA-4-P and point to cAMP/cGMP as potential targets for improving VDA activity. Acknowledgements Funded by Cancer Research UK
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signaling interactions between rhogtpase and camp cgmp influence endothelial responses to the vascular disrupting agent Combretastatin A4 Phosphate
2010Co-Authors: Chryso Kanthou, Constantino Carlos Reyesaldasoro, Gillian M. TozerAbstract:Background: Combretastatin A4 Phosphate (CA4P) is a tumour vascular disrupting agent (VDA) that targets endothelial microtubules, triggering remodelling of the actin cytoskeleton, contractility and disruption of VE-cadherin junctions through RhoGTPase/ROCK-dependent pathways. These events lead to a rise in endothelial monolayer permeability. A rise in permeability is considered crucial for vascular shutdown elicited by CA4P in vivo. CA4P also inhibits endothelial migration and induces mitotic arrest and apoptosis, so potentially it could also target tumour angiogenesis. Method: In this study, the nature of signalling interactions between Rho/ROCK and cAMP/cGMP and their influence on cytoskeletal and functional responses of endothelial cells to CA4P were investigated. Results: Several cAMP/cGMP analogues inhibited CA4P-induced Rho/ROCK activation and prevented actin remodeling, disruption of cell-to-cell junctions and permeability rise in endothelial monolayers. cAMP inhibits Rho by either protein kinase A (PKA)-dependent mechanisms or via activation of Epac1/Rap1. O-Me-cAMP, an analogue that selectively activates Epac1/Rap1 abolished activation of Rho/ROCK by CA4P while selective PKA activator 6-Bnz-cAMP only partially inhibited Rho/ROCK activation and actin remodelling by CA4P. Inhibitors of PKA did not alter endothelial responses to CA4P in the presence of cAMP analogues suggesting that cAMP acts primarily via Epac1/Rap1 to inhibit Rho/CA4P interactions. CA-4-P also inhibited endothelial migration and abolished lamellipodia at the leading edge of migrating cells in injured monolayers. Rho inhibitor C3 exoenzyme and ROCK inhibitor Y27632 as well as cAMP analogues re-established cell movement and formation of lamellipodia in wounded monolayers exposed to CA-4-P, suggesting that inhibitory effects on migration were mediated via Rho/ROCK. Conclusion: Deciphering molecular pathways that modulate endothelial responses to VDAs is important for further targeting. Our data demonstrate that interactions between cGMP/cAMP and Rho influence both the vascular disrupting and anti-angiogenic activities of CA-4-P and point to cAMP/cGMP as potential targets for improving VDA activity. Acknowledgements Funded by Cancer Research UK
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A critical role for RhoA-GTPase signaling in the tumour vascular disrupting action of Combretastatin A4-Phosphate in vivo
2010Co-Authors: L. J. Williams, Matthew Fisher, Chryso Kanthou, Constantino Carlos Reyes-aldasoro, Gillian M. TozerAbstract:Background: Tubulin binding microtubule depolymerising agents form a growing group of tumour vascular disrupting agents (VDAs) in clinical trial, with Combretastatin A-4-Phosphate (CA4P) the lead compound. Signalling through RhoGTPase/ROCK-dependent pathways is central to CA4P-induced effects on endothelial cells in vitro (Kanthou C. & Tozer GM, 2002, Blood 99: 2060-2069) . Here, we tested the hypothesis that RhoGTPase/ROCK signalling is also important in vivo. Method: SW1222 human colorectal carcinoma cells were grown as solid sub-cutaneous tumours in SCID mice. The Rho kinase (ROCK) inhibitor, Y-27632 (50 mg/kg) or saline control, was administered intraperitoneally (i.p.), 5 minutes prior to 100 mg/kg CA4P or saline i.p.. Laser Doppler flowmetry was used to assess tumour vascular response from 0 – 2h post-treatment. Intravenous administration of fluorescent tomato lectin was used for assessing tumour perfusion at 1, 3, 6 and 24 hours post-treatment. Necrosis (H&E) and leukocyte infiltration (immunohistochemistry) were assessed at 24h. Results: Y-27632 alone did not significantly increase necrosis at 24 hours (17±4% versus 10±3% of tumour sectional area). However, prior administration of Y-27632 significantly reduced CA4P-induced tumour necrosis from 61±5% to 35±7%, accompanied by a decrease in staining for the myeloid markers, myeloperoxidase and GR-1. Y-27632 pre-treatment did not affect laser Doppler and perfused vascular volume measurements in the first few hours after CA4P but significantly reduced the effect of CA4P on perfused vascular volume measured at 6 and 24 hours. Conclusion: Our data indicate that RhoGTPase/ROCK-dependent signalling is a critical factor in determining extent of tumour necrosis induction by CA4P and suggest that ROCK inhibition is acting downstream from initial vascular shut-down, potentially via modulation of myeloid cell recruitment. These mechanisms also have significance for similar VDAs in development. Funded by Cancer Research UK
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Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2003Co-Authors: Susan M. Galbraith, Gillian M. Tozer, Luiza Sena, Ross J. Maxwell, Martin A. Lodge, John Wilson, N. Jane Taylor, J. James Stirling, Anwar R. Padhani, Gordon J. S. RustinAbstract:Purpose: Combretastatin A4 Phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. Materials and Methods: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions wer...