The Experts below are selected from a list of 1938 Experts worldwide ranked by ideXlab platform
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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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)
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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)
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Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo.
Cancer Science, 2003Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Toshi Horiuchi, Yasuhiro Koh, Nami Fujio, Yuichiro Ohe, Nagahiro Saijo, Kazuto Nishio, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), an Antimicrotubule Agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of Antimicrotubule Agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these Agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these Agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
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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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)
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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)
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Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo.
Cancer Science, 2003Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Toshi Horiuchi, Yasuhiro Koh, Nami Fujio, Yuichiro Ohe, Nagahiro Saijo, Kazuto Nishio, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), an Antimicrotubule Agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of Antimicrotubule Agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these Agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these Agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
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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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)
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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)
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Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo.
Cancer Science, 2003Co-Authors: Tsugitaka Natsume, Junichi Watanabe, Toshi Horiuchi, Yasuhiro Koh, Nami Fujio, Yuichiro Ohe, Nagahiro Saijo, Kazuto Nishio, Motohiro KobayashiAbstract:TZT-1027 (Soblidotin), an Antimicrotubule Agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of Antimicrotubule Agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these Agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these Agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
Bradley S. Davidson - One of the best experts on this subject based on the ideXlab platform.
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an improved synthesis of the c15 c28 fragment of laulimalide
Tetrahedron Letters, 2002Co-Authors: A. Sivaramakrishnan, Geoffry T. Nadolski, Ian Mcalexander, Bradley S. DavidsonAbstract:Abstract The C 15 –C 28 fragment of the paclitaxel-like Antimicrotubule Agent laulimalide has been synthesized in 12 linear steps from known epoxide 5 , with an overall yield of 16%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin metathesis chemistry. The 19,20-diol stereochemistry originates in starting material 7 and the side chain was appended using a Kocienski-modified Julia coupling.
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An improved synthesis of the C15–C28 fragment of laulimalide
Tetrahedron Letters, 2002Co-Authors: A. Sivaramakrishnan, Geoffry T. Nadolski, Ian Mcalexander, Bradley S. DavidsonAbstract:Abstract The C 15 –C 28 fragment of the paclitaxel-like Antimicrotubule Agent laulimalide has been synthesized in 12 linear steps from known epoxide 5 , with an overall yield of 16%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin metathesis chemistry. The 19,20-diol stereochemistry originates in starting material 7 and the side chain was appended using a Kocienski-modified Julia coupling.
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synthetic studies toward the microtubule stabilizing Agent laulimalide synthesis of the c15 c28 fragment
Tetrahedron Letters, 2001Co-Authors: Travis B Messenger, Bradley S. DavidsonAbstract:Abstract The C 15 –C 28 fragment of the paclitaxel-like Antimicrotubule Agent laulimalide has been synthesized in 12 linear steps with an overall yield of 14%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin metathesis chemistry and the 19,20- syn -diol was generated through the addition of a mixed vinyl zincate to a protected α-hydroxyaldehyde.
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Synthetic studies toward the microtubule-stabilizing Agent laulimalide: synthesis of the C15–C28 fragment
Tetrahedron Letters, 2001Co-Authors: B. Travis Messenger, Bradley S. DavidsonAbstract:Abstract The C 15 –C 28 fragment of the paclitaxel-like Antimicrotubule Agent laulimalide has been synthesized in 12 linear steps with an overall yield of 14%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin metathesis chemistry and the 19,20- syn -diol was generated through the addition of a mixed vinyl zincate to a protected α-hydroxyaldehyde.
Ian E Krop - One of the best experts on this subject based on the ideXlab platform.
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trastuzumab emtansine a novel antibody drug conjugate for her2 positive breast cancer
Clinical Cancer Research, 2014Co-Authors: Ian E Krop, Eric P WinerAbstract:Trastuzumab emtansine (T-DM1) is a novel HER2-directed antibody–drug conjugate. T-DM1 consists of the potent Antimicrotubule Agent DM1, linked via a noncleavable linker to the HER2-specific monoclonal antibody trastuzumab. Preclinical studies demonstrate that T-DM1 has dual mechanisms of action: selective delivery of DM1 to the HER2-positive (HER2 + ) tumor cell combined with trastuzumab9s activation of antibody-dependent cell-mediated cytotoxicity and inhibition of HER2-mediated signal transduction. In phase II studies, T-DM1 was active in patients with trastuzumab- and lapatinib-refractory metastatic breast cancer and led to improved progression-free survival compared with the combination of trastuzumab and docetaxel in the first-line setting. In a recent phase III trial in patients with metastatic breast cancer who previously received trastuzumab and a taxane, T-DM1 resulted in improved progression-free and overall survival compared with capecitabine and lapatinib. T-DM1 is associated with a favorable toxicity profile; reversible thrombocytopenia and hepatic transaminase elevations are the only grade ≥3 adverse event present in 5% or more of patients. Alopecia, peripheral neuropathy, and neutropenia are distinctly uncommon. On the basis of its improved efficacy and toxicity compared with capecitabine/lapatinib, T-DM1 should be considered the standard for patients with HER2 + metastatic breast cancer who have previously progressed on trastuzumab and a taxane. Results from additional randomized studies in metastatic breast cancer are pending, and trials in the (neo)adjuvant setting are being initiated. Clin Cancer Res; 20(1); 15–20. ©2013 AACR .
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a phase ii study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer who were previously treated with trastuzumab lapatinib an anthracycline a taxane and capecitabine
Journal of Clinical Oncology, 2012Co-Authors: Ian E Krop, Patricia Lorusso, Kathy D Miller, Shanu Modi, Denise A Yardley, Gladys Rodriguez, Ellie Guardino, Michael Lu, Maoxia Zheng, Sandhya GirishAbstract:Purpose To determine whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) –targeted delivery of the potent Antimicrotubule Agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-positive metastatic breast cancer (MBC) who have previously received all standard HER2-directed therapies. Patients and Methods In this single-arm phase II study, T-DM1 3.6 mg/kg was administered intravenously every 3 weeks to patients with HER2-positive MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety. Results Among 110 pretreated patients (median, seven prior Agents for MBC; median follow-up, 17.4 months), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clinical benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 months (95% CI, 4.2 to 8.4 ...
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phase ii study of the antibody drug conjugate trastuzumab dm1 for the treatment of human epidermal growth factor receptor 2 her2 positive breast cancer after prior her2 directed therapy
Journal of Clinical Oncology, 2011Co-Authors: Howard A Burris, Ian E Krop, Hope S Rugo, Svetislava J Vukelja, Charles L Vogel, Rachel A Borson, Steven A Limentani, Elizabeth Tanchiu, Richard Alan Michaelson, Sandhya GirishAbstract:Purpose The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent Antimicrotubule Agent, DM1, to human epidermal growth factor receptor 2 (HER2) –overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. Patients and Methods This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. Results With a follow-up of ≥ 12 months among 112 treated patients, the objecti...
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phase i study of trastuzumab dm1 an her2 antibody drug conjugate given every 3 weeks to patients with her2 positive metastatic breast cancer
Journal of Clinical Oncology, 2010Co-Authors: Ian E Krop, S N Holden, Jay Tibbitts, Shanu Modi, Sandhya Girish, M Beeram, Suzanne F Jones, Wei Yu, Joohee Yi, Mark X SliwkowskiAbstract:Purpose Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid Antimicrotubule Agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Patients and Methods Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Results Twenty-four patients who had received a median of four prior chemotherapeutic Agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) inclu...