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Motohiro Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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tumor specific Antivascular effect of tzt 1027 soblidotin elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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The inhibitory effect of docetaxel and p38 MAPK inhibitor on TZT-1027 (Soblidotin)-induced Antivascular activity.
Anticancer research, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:BACKGROUND: TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has Antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced Antivascular activity by investigating the impact of various inhibitors. MATERIALS AND METHODS: The inhibitory effects on TZT-1027-induced Antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of Antivascular activity. RESULTS: Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of alpha-tubulin an effect opposite to that of TZT-1027. CONCLUSION: TZT-1027-induced Antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.
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Comparison of the Antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents.
Anti-cancer drugs, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), a microtubule-depolymerizing agent exerts both a direct cytotoxic activity against cancer cells and an indirect Antivascular activity against tumor vascular endothelial cells. We compared both activities of TZT-1027 with those of various anticancer agents having different mechanisms of action, including vinca alkaloids, a vascular targeting agent, a taxane and nonmicrotubule-binding agents. In the MTT assay, TZT-1027 most potently inhibited the growth of both murine colon C26 cancer cells and human umbilical vein endothelial cells, implying its potent Antivascular activity against tumor vasculature in addition to its cytotoxic activity against cancer cells. Treatment with 0.1 microg/ml TZT-1027 significantly enhanced vascular permeability in human umbilical vein endothelial cell monolayers and a single intravenous administration of 2 mg/kg TZT-1027 significantly reduced the perfusion of Colon26 tumors implanted into mice, with efficacies superior to vinca alkaloids and comparable to a known vascular targeting agent. These results strongly suggest that TZT-1027 exerts marked Antivascular activity. Next, to clarify the mechanism of the Antivascular activity, we have taken a novel approach, and analyzed the relationships among human umbilical vein endothelial cells cytotoxicity, vascular permeability and tumor perfusion, on the basis of efficacies of each agent. Analyses revealed strong and significant correlations, and indicated that the vascular endothelial cell damage leads to endothelial barrier dysfunction and, thereby, tumor vascular shutdown. In summary, TZT-1027 was verified to have not only an excellent cytotoxic activity, but also an attractive Antivascular activity through the induction of damage to vascular endothelial cells. We believe that these dual activities may make TZT-1027 useful for treating solid tumors.
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Tumor‐specific Antivascular effect of TZT‐1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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Antivascular effects of tzt 1027 soblidotin on murine colon26 adenocarcinoma
Cancer Science, 2006Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce Antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10−7 g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses Antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its Antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect Antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors. (Cancer Sci 2006; 97: 1410–1416)
Junichi Watanabe - One of the best experts on this subject based on the ideXlab platform.
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tumor specific Antivascular effect of tzt 1027 soblidotin elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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The inhibitory effect of docetaxel and p38 MAPK inhibitor on TZT-1027 (Soblidotin)-induced Antivascular activity.
Anticancer research, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:BACKGROUND: TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has Antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced Antivascular activity by investigating the impact of various inhibitors. MATERIALS AND METHODS: The inhibitory effects on TZT-1027-induced Antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of Antivascular activity. RESULTS: Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of alpha-tubulin an effect opposite to that of TZT-1027. CONCLUSION: TZT-1027-induced Antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.
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Comparison of the Antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents.
Anti-cancer drugs, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), a microtubule-depolymerizing agent exerts both a direct cytotoxic activity against cancer cells and an indirect Antivascular activity against tumor vascular endothelial cells. We compared both activities of TZT-1027 with those of various anticancer agents having different mechanisms of action, including vinca alkaloids, a vascular targeting agent, a taxane and nonmicrotubule-binding agents. In the MTT assay, TZT-1027 most potently inhibited the growth of both murine colon C26 cancer cells and human umbilical vein endothelial cells, implying its potent Antivascular activity against tumor vasculature in addition to its cytotoxic activity against cancer cells. Treatment with 0.1 microg/ml TZT-1027 significantly enhanced vascular permeability in human umbilical vein endothelial cell monolayers and a single intravenous administration of 2 mg/kg TZT-1027 significantly reduced the perfusion of Colon26 tumors implanted into mice, with efficacies superior to vinca alkaloids and comparable to a known vascular targeting agent. These results strongly suggest that TZT-1027 exerts marked Antivascular activity. Next, to clarify the mechanism of the Antivascular activity, we have taken a novel approach, and analyzed the relationships among human umbilical vein endothelial cells cytotoxicity, vascular permeability and tumor perfusion, on the basis of efficacies of each agent. Analyses revealed strong and significant correlations, and indicated that the vascular endothelial cell damage leads to endothelial barrier dysfunction and, thereby, tumor vascular shutdown. In summary, TZT-1027 was verified to have not only an excellent cytotoxic activity, but also an attractive Antivascular activity through the induction of damage to vascular endothelial cells. We believe that these dual activities may make TZT-1027 useful for treating solid tumors.
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Tumor‐specific Antivascular effect of TZT‐1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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Antivascular effects of tzt 1027 soblidotin on murine colon26 adenocarcinoma
Cancer Science, 2006Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce Antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10−7 g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses Antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its Antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect Antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors. (Cancer Sci 2006; 97: 1410–1416)
Tsugitaka Natsume - One of the best experts on this subject based on the ideXlab platform.
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tumor specific Antivascular effect of tzt 1027 soblidotin elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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The inhibitory effect of docetaxel and p38 MAPK inhibitor on TZT-1027 (Soblidotin)-induced Antivascular activity.
Anticancer research, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:BACKGROUND: TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has Antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced Antivascular activity by investigating the impact of various inhibitors. MATERIALS AND METHODS: The inhibitory effects on TZT-1027-induced Antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of Antivascular activity. RESULTS: Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of alpha-tubulin an effect opposite to that of TZT-1027. CONCLUSION: TZT-1027-induced Antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.
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Comparison of the Antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents.
Anti-cancer drugs, 2007Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), a microtubule-depolymerizing agent exerts both a direct cytotoxic activity against cancer cells and an indirect Antivascular activity against tumor vascular endothelial cells. We compared both activities of TZT-1027 with those of various anticancer agents having different mechanisms of action, including vinca alkaloids, a vascular targeting agent, a taxane and nonmicrotubule-binding agents. In the MTT assay, TZT-1027 most potently inhibited the growth of both murine colon C26 cancer cells and human umbilical vein endothelial cells, implying its potent Antivascular activity against tumor vasculature in addition to its cytotoxic activity against cancer cells. Treatment with 0.1 microg/ml TZT-1027 significantly enhanced vascular permeability in human umbilical vein endothelial cell monolayers and a single intravenous administration of 2 mg/kg TZT-1027 significantly reduced the perfusion of Colon26 tumors implanted into mice, with efficacies superior to vinca alkaloids and comparable to a known vascular targeting agent. These results strongly suggest that TZT-1027 exerts marked Antivascular activity. Next, to clarify the mechanism of the Antivascular activity, we have taken a novel approach, and analyzed the relationships among human umbilical vein endothelial cells cytotoxicity, vascular permeability and tumor perfusion, on the basis of efficacies of each agent. Analyses revealed strong and significant correlations, and indicated that the vascular endothelial cell damage leads to endothelial barrier dysfunction and, thereby, tumor vascular shutdown. In summary, TZT-1027 was verified to have not only an excellent cytotoxic activity, but also an attractive Antivascular activity through the induction of damage to vascular endothelial cells. We believe that these dual activities may make TZT-1027 useful for treating solid tumors.
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Tumor‐specific Antivascular effect of TZT‐1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy
Cancer Science, 2007Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Kenji Ogawa, Kazuhiko Yasumura, Motohiro KobayashiAbstract:TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its Antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the Antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable Antivascular effect in addition to an excellent cytotoxic effect.
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Antivascular effects of tzt 1027 soblidotin on murine colon26 adenocarcinoma
Cancer Science, 2006Co-Authors: Junichi Watanabe, Tsugitaka Natsume, Motohiro KobayashiAbstract:We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce Antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10−7 g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses Antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its Antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect Antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors. (Cancer Sci 2006; 97: 1410–1416)
Chandra M. Sehgal - One of the best experts on this subject based on the ideXlab platform.
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Antivascular ultrasound therapy: magnetic resonance imaging validation and activation of the immune response in murine melanoma.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2015Co-Authors: Stephen J. Hunt, Terence P. Gade, Michael C. Soulen, Stephen Pickup, Chandra M. SehgalAbstract:Objectives The purpose of this study was to investigate the treatment effects of Antivascular ultrasound (US) with dynamic contrast-enhanced magnetic resonance imaging (MRI), contrast-enhanced sonography, and histopathologic analysis in a murine melanoma model. Methods Subcutaneous K1735 murine melanoma tumors were grown in syngeneic C3H/HeN mice. Quantitative tumor perfusion characteristics were measured before Antivascular US treatment with both dynamic contrast-enhanced MRI and high-resolution contrast-enhanced sonography. Tumors were subsequently treated with 1 or 3 minutes of continuous low-intensity US after intravenous administration of a US contrast agent. Treatment effects were assessed by quantitative dynamic contrast-enhanced MRI, contrast-enhanced sonography, histopathologic analysis, and immunohistochemistry. Results Low-intensity Antivascular US treatment resulted in approximately a doubling and tripling of the time to peak enhancement on dynamic contrast-enhanced MRI in the 1- and 3-minute treatment groups, respectively, along with a significant decrease in contrast wash-out (P < .01). There was a potent reduction in tumor perfusion on contrast-enhanced sonography, with approximately 40% and 70% reductions in the tumor area perfused as assessed by contrast-enhanced sonography after 1 (P < .05) and 3 (P < .01) minutes of Antivascular US. The pathologic and histologic changes spatially correlated with the regions of diminished perfusion seen on contrast-enhanced sonography and dynamic contrast-enhanced MRI. Antivascular US therapy resulted in a significant increase in the number of hypoxia-inducible factor 1A+ cells, indicating tumor hypoxia (P < .01), and of CD45+/CD3+ cells in tumors after treatment, in keeping with increased T-cell infiltration (P < .01). Conclusions Antivascular US treatment effects extend beyond direct cytotoxicity from hemorrhagic necrosis to include ischemia-mediated cytotoxicity, enhanced small molecule retention, and intratumoral immune activation.
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TU‐C‐144‐02: Antivascular Ultrasound for Cancer Treatment: The Role of Thermal Effects
Medical Physics, 2013Co-Authors: Chandra M. Sehgal, Stephen J. Hunt, Benjamin J. Levenback, Andrew K.w. WoodAbstract:Purpose: Tour previous studies1 have demonstrated that low‐intensity ultrasound (1∼2 W/cm2, 0.2‐0.3 MPa) in the presence of microbubbles disrupt tumor vasculature and behaves as an Antivascular agent for the treatment of cancer. Although the Antivascular effect is potent and reproducible, the mechanism of action is not fully understood. The goal of this study we evaluate the role of thermal effects in Antivascular ultrasound. Methods: Studies were performed in mice with subcutaneous melanoma (K1735). Antivascular ultrasound (AVUS) therapy was performed at 1 and 3 MHz. During treatment temperature was measured with a fine wire thermocouple. Tumor vascularity (percentage area of perfusion, PAF) was assessed before and after each test and sham treatment with contrast‐enhanced Doppler US imaging. Simulations of microbubble induced heating were performed for mono‐and polydisperse (lognormal distribution) microbubbles under varying conditions of experiments and blood flowResults and Conclusions: AVUS reduced the tumor vascularity at both 1 MHz and 3 MHz. The vascularity reduction at 3 MHz was two times greater than with 1 MHz treatment. The enhanced Antivascular action at 3 MHz was significant (P=0.02). The measured temperature increase was 5.2 ± 1.4°C for the 1 MHz ultrasound and 10.2 ± 2.7°C for 3 MHz ultrasound. Consistent with the experimental observations modeling showed that microbubble induced temperature increased more rapidly at 3 MHz than at 1 MHz. The observation that there is greater neovascular disruption and temperature change 3 MHz than at 1 MHz suggests that the ultrasound Antivascular activity is primarily thermal in nature, although inertial cavitational effects cannot be excluded. The tissue response to Antivascular ultrasound injuries could further stimulate an immune response and induce endogenous vaccination.1. Wood et al, Acad. Rad., 15, 1133, 2008; Levenback et al, JASA, 131, 540, 2012; IEEE Ultrasonics 2012.
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Modeling of thermal effects in Antivascular ultrasound therapy
The Journal of the Acoustical Society of America, 2012Co-Authors: Benjamin J. Levenback, Chandra M. Sehgal, Andrew K.w. WoodAbstract:Antivascular ultrasound consisting of low-intensity sonication in the presence of circulating microbubbles of an ultrasound contrast agent has been demonstrated to disrupt blood flow in solid cancers. In this study a mathematical framework is described for the microbubble-induced heating that occurs during Antivascular ultrasound. Biological tissues are modeled as a continuum of microbubble-filled vasculature, cells, and interstitial fluids with compressibility equal to the sum of the compressibility of each component. The mathematical simulations show that the absorption of ultrasound waves by viscous damping of the microbubble oscillations induced significant local heating of the tissue vasculature. The extent and the rate of temperature increase not only depends on the properties of the microbubbles and the sonication parameters but is also influenced markedly by the blood flow. Slow flow conditions lead to higher tissue temperatures due to a stronger interaction between microbubbles and ultrasound and reduced heat dissipation. Because tumors have slower blood flow than healthy tissue, the microbubble-induced ultrasound Antivascular therapy is likely to affect cancerous tissue more extensively than healthy tissue, providing a way to selectively target the vasculature of cancers.
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Antivascular Ultrasound Therapy Extends Survival of Mice With Implanted Melanomas
Ultrasound in medicine & biology, 2010Co-Authors: Andrew K.w. Wood, Susan M. Schultz, William M. F. Lee, Ralph M. Bunte, Chandra M. SehgalAbstract:Abstract The goal of this murine investigation was to evaluate the effect of an Antivascular ultrasound treatment on the growth of an implanted melanoma and the consequent survival rate. After the intravenous injection of 0.2 mL ultrasound contrast agent (Definity), therapy ( n = 15) was performed on 1-mL tumors for 3 min with low-intensity continuous ultrasound (3 MHz; 2.4 ± 0.1 W.cm –2 [I SATA ]); control mice ( n = 17) received a sham treatment. Mice were euthanized once the tumor had reached 3 mL, and then survival percentage vs. time curves were plotted. The median survival time (time for tumor to reach 3 mL) for the treated group was 23 d and for the control group was 18 d; the difference was statistically significant ( p ≤ 0.0001). Antivascular ultrasound therapy reduced the growth rate of an implanted melanoma and increased survival time. The ultrasound therapy provides a further example of tumor vascular disruption, and its future clinical potential should be investigated. (E-mail: sehgalc@uphs.upenn.edu )
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The Antivascular action of physiotherapy ultrasound on a murine tumor: role of a microbubble contrast agent.
Ultrasound in medicine & biology, 2007Co-Authors: Andrew K.w. Wood, William M. F. Lee, Ralph M. Bunte, Jennie D. Cohen, Jeff H. Tsai, Chandra M. SehgalAbstract:This study investigated whether a microbubble-containing ultrasound contrast agent had a role in the Antivascular action of physiotherapy ultrasound on tumor neovasculature. Ultrasound images (B-mode and contrast-enhanced power Doppler (0.02 mL Definity)) were made of 22 murine melanomas (K1735 22 ). The tumor was insonated (ISATA 1.7 Wc m -2 , 1 MHz, continuous output) for 3 min and the power Doppler observations of the pre- and postinsonation tumor vascularities were analyzed. Significant reductions (p 0.005 for analyses of color-weighted fractional area) in vascularity occurred when a contrast-enhanced power Doppler study occurred before insonation. Vascularity was unchanged in tumors without a pretherapy Doppler study. Histo- logic studies revealed tissue structural changes that correlated with the ultrasound findings. The underlying etiology of the interaction between the physiotherapy ultrasound beam, the microbubble-containing contrast agent and the tumor neovasculature is unknown. It was concluded that contrast agents play an important role in the Antivascular effects induced by physiotherapy ultrasound. (E-mail: sehgalc@uphs.upenn.edu) © 2007 World Federation for Ultrasound in Medicine & Biology.
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TU‐C‐144‐02: Antivascular Ultrasound for Cancer Treatment: The Role of Thermal Effects
Medical Physics, 2013Co-Authors: Chandra M. Sehgal, Stephen J. Hunt, Benjamin J. Levenback, Andrew K.w. WoodAbstract:Purpose: Tour previous studies1 have demonstrated that low‐intensity ultrasound (1∼2 W/cm2, 0.2‐0.3 MPa) in the presence of microbubbles disrupt tumor vasculature and behaves as an Antivascular agent for the treatment of cancer. Although the Antivascular effect is potent and reproducible, the mechanism of action is not fully understood. The goal of this study we evaluate the role of thermal effects in Antivascular ultrasound. Methods: Studies were performed in mice with subcutaneous melanoma (K1735). Antivascular ultrasound (AVUS) therapy was performed at 1 and 3 MHz. During treatment temperature was measured with a fine wire thermocouple. Tumor vascularity (percentage area of perfusion, PAF) was assessed before and after each test and sham treatment with contrast‐enhanced Doppler US imaging. Simulations of microbubble induced heating were performed for mono‐and polydisperse (lognormal distribution) microbubbles under varying conditions of experiments and blood flowResults and Conclusions: AVUS reduced the tumor vascularity at both 1 MHz and 3 MHz. The vascularity reduction at 3 MHz was two times greater than with 1 MHz treatment. The enhanced Antivascular action at 3 MHz was significant (P=0.02). The measured temperature increase was 5.2 ± 1.4°C for the 1 MHz ultrasound and 10.2 ± 2.7°C for 3 MHz ultrasound. Consistent with the experimental observations modeling showed that microbubble induced temperature increased more rapidly at 3 MHz than at 1 MHz. The observation that there is greater neovascular disruption and temperature change 3 MHz than at 1 MHz suggests that the ultrasound Antivascular activity is primarily thermal in nature, although inertial cavitational effects cannot be excluded. The tissue response to Antivascular ultrasound injuries could further stimulate an immune response and induce endogenous vaccination.1. Wood et al, Acad. Rad., 15, 1133, 2008; Levenback et al, JASA, 131, 540, 2012; IEEE Ultrasonics 2012.
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Modeling of thermal effects in Antivascular ultrasound therapy
The Journal of the Acoustical Society of America, 2012Co-Authors: Benjamin J. Levenback, Chandra M. Sehgal, Andrew K.w. WoodAbstract:Antivascular ultrasound consisting of low-intensity sonication in the presence of circulating microbubbles of an ultrasound contrast agent has been demonstrated to disrupt blood flow in solid cancers. In this study a mathematical framework is described for the microbubble-induced heating that occurs during Antivascular ultrasound. Biological tissues are modeled as a continuum of microbubble-filled vasculature, cells, and interstitial fluids with compressibility equal to the sum of the compressibility of each component. The mathematical simulations show that the absorption of ultrasound waves by viscous damping of the microbubble oscillations induced significant local heating of the tissue vasculature. The extent and the rate of temperature increase not only depends on the properties of the microbubbles and the sonication parameters but is also influenced markedly by the blood flow. Slow flow conditions lead to higher tissue temperatures due to a stronger interaction between microbubbles and ultrasound and reduced heat dissipation. Because tumors have slower blood flow than healthy tissue, the microbubble-induced ultrasound Antivascular therapy is likely to affect cancerous tissue more extensively than healthy tissue, providing a way to selectively target the vasculature of cancers.
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Antivascular Ultrasound Therapy Extends Survival of Mice With Implanted Melanomas
Ultrasound in medicine & biology, 2010Co-Authors: Andrew K.w. Wood, Susan M. Schultz, William M. F. Lee, Ralph M. Bunte, Chandra M. SehgalAbstract:Abstract The goal of this murine investigation was to evaluate the effect of an Antivascular ultrasound treatment on the growth of an implanted melanoma and the consequent survival rate. After the intravenous injection of 0.2 mL ultrasound contrast agent (Definity), therapy ( n = 15) was performed on 1-mL tumors for 3 min with low-intensity continuous ultrasound (3 MHz; 2.4 ± 0.1 W.cm –2 [I SATA ]); control mice ( n = 17) received a sham treatment. Mice were euthanized once the tumor had reached 3 mL, and then survival percentage vs. time curves were plotted. The median survival time (time for tumor to reach 3 mL) for the treated group was 23 d and for the control group was 18 d; the difference was statistically significant ( p ≤ 0.0001). Antivascular ultrasound therapy reduced the growth rate of an implanted melanoma and increased survival time. The ultrasound therapy provides a further example of tumor vascular disruption, and its future clinical potential should be investigated. (E-mail: sehgalc@uphs.upenn.edu )
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The Antivascular action of physiotherapy ultrasound on a murine tumor: role of a microbubble contrast agent.
Ultrasound in medicine & biology, 2007Co-Authors: Andrew K.w. Wood, William M. F. Lee, Ralph M. Bunte, Jennie D. Cohen, Jeff H. Tsai, Chandra M. SehgalAbstract:This study investigated whether a microbubble-containing ultrasound contrast agent had a role in the Antivascular action of physiotherapy ultrasound on tumor neovasculature. Ultrasound images (B-mode and contrast-enhanced power Doppler (0.02 mL Definity)) were made of 22 murine melanomas (K1735 22 ). The tumor was insonated (ISATA 1.7 Wc m -2 , 1 MHz, continuous output) for 3 min and the power Doppler observations of the pre- and postinsonation tumor vascularities were analyzed. Significant reductions (p 0.005 for analyses of color-weighted fractional area) in vascularity occurred when a contrast-enhanced power Doppler study occurred before insonation. Vascularity was unchanged in tumors without a pretherapy Doppler study. Histo- logic studies revealed tissue structural changes that correlated with the ultrasound findings. The underlying etiology of the interaction between the physiotherapy ultrasound beam, the microbubble-containing contrast agent and the tumor neovasculature is unknown. It was concluded that contrast agents play an important role in the Antivascular effects induced by physiotherapy ultrasound. (E-mail: sehgalc@uphs.upenn.edu) © 2007 World Federation for Ultrasound in Medicine & Biology.