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Teruhiro Utsugi – One of the best experts on this subject based on the ideXlab platform.

  • abstract c128 tas 116 an orally available hsp90α β selective inhibitor has potent antitumor activity in small cell lung cancer as a single agent and in combination with an Anthracycline Derivative amrubicin
    Molecular Cancer Therapeutics, 2013
    Co-Authors: Hiromi Muraoka, Chihoko Yoshimura, Akihiro Hashimoto, Kenjiro Ito, Makoto Kitade, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi

    Abstract:

    Background: The molecular chaperone HSP90 has been considered a promising target for cancer therapy. We have previously reported the discovery of an orally available HSP90α/β selective inhibitor, TAS-116. TAS-116 led to tumor shrinkage in various human tumor xenograft models, while not inducing retinal toxicity in rats including at doses given above the maximum tolerated dose. Extensive small cell lung cancer (SCLC) is one of the most aggressive types of cancer, and has an unmet medical need for more effective treatments. An Anthracycline, amrubicin (AMR), has been used to treat platinum resistant SCLC in Japan. Here we report on the possible application of TAS-116 to treat SCLC both as a single agent and in combination with AMR. Materials and Methods: In vitro drug combination effects were evaluated with calculation of the combination index and cell cycle analysis by fluorescence-activated cell sorting. To clarify the mechanism involved in TAS-116’s enhancement of Anthracycline-induced apoptosis the extent of apoptosis was measured in combination with several kinase inhibitors including SB 218078 (CHK1) and MK-2206 (AKT). Antitumor activities of TAS-116 alone and in combination with AMR were evaluated in human SCLC xenograft models. Results: TAS-116 induced cell growth arrest and apoptosis in SCLC cell lines by inhibiting both PI3K/AKT and MAPK signaling through downregulation of HSP90 clients such as AKT and RAF1. TAS-116 also showed antitumor activity against human SCLC tumor xenograft models. In in vitro explorative combination studies in SCLC cell lines, structurally-related Anthracyclines, AMR and doxorubicin (DOX), both showed synergistic effect upon apoptosis induction in combination with TAS-116. Moreover, TAS-116 enhanced the antitumor activity of AMR in human SCLC tumor xenograft models. Since Anthracyclines exert antitumor activity based on their DNA damaging potential through topoisomerase II inhibition, we evaluated whether DNA damage signaling proteins and apoptosis-related proteins were affected by TAS-116 when given in combination with DOX. TAS-116 significantly reduced phosphorylation of CHK1, AKT and ERK1/2. In combination with these kinase inhibitors, SB 218078 significantly and MK-2206 moderately enhanced DOX-mediated apoptosis. Comparatively, TAS-116 enhanced apoptosis to a greater extent than SB 218078. Conclusion: TAS-116 showed antitumor activity against human SCLC tumor xenograft models alone and in combination with AMR. Our data suggest that TAS-116 enhanced the antitumor activity of Anthracyclines through the combined actions of abrogation of the DNA damage-induced G2/M checkpoint and the inhibition of a survival signal by CHK1 and AKT downregulation, respectively. These results suggest that TAS-116 could be a promising agent to treat extensive SCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C128. Citation Format: Hiromi Muraoka, Chihoko Yoshimura, Akihiro Hashimoto, Kenjiro Ito, Makoto Kitade, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi. TAS-116, an orally available HSP90α/β selective inhibitor, has potent antitumor activity in small cell lung cancer as a single agent and in combination with an Anthracycline Derivative, amrubicin. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C128.

  • Abstract C128: TAS-116, an orally available HSP90α/β selective inhibitor, has potent antitumor activity in small cell lung cancer as a single agent and in combination with an Anthracycline Derivative, amrubicin.
    Heat Shock Proteins, 2013
    Co-Authors: Hiromi Muraoka, Chihoko Yoshimura, Akihiro Hashimoto, Kenjiro Ito, Makoto Kitade, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi

    Abstract:

    Background: The molecular chaperone HSP90 has been considered a promising target for cancer therapy. We have previously reported the discovery of an orally available HSP90α/β selective inhibitor, TAS-116. TAS-116 led to tumor shrinkage in various human tumor xenograft models, while not inducing retinal toxicity in rats including at doses given above the maximum tolerated dose. Extensive small cell lung cancer (SCLC) is one of the most aggressive types of cancer, and has an unmet medical need for more effective treatments. An Anthracycline, amrubicin (AMR), has been used to treat platinum resistant SCLC in Japan. Here we report on the possible application of TAS-116 to treat SCLC both as a single agent and in combination with AMR. Materials and Methods: In vitro drug combination effects were evaluated with calculation of the combination index and cell cycle analysis by fluorescence-activated cell sorting. To clarify the mechanism involved in TAS-116’s enhancement of Anthracycline-induced apoptosis the extent of apoptosis was measured in combination with several kinase inhibitors including SB 218078 (CHK1) and MK-2206 (AKT). Antitumor activities of TAS-116 alone and in combination with AMR were evaluated in human SCLC xenograft models. Results: TAS-116 induced cell growth arrest and apoptosis in SCLC cell lines by inhibiting both PI3K/AKT and MAPK signaling through downregulation of HSP90 clients such as AKT and RAF1. TAS-116 also showed antitumor activity against human SCLC tumor xenograft models. In in vitro explorative combination studies in SCLC cell lines, structurally-related Anthracyclines, AMR and doxorubicin (DOX), both showed synergistic effect upon apoptosis induction in combination with TAS-116. Moreover, TAS-116 enhanced the antitumor activity of AMR in human SCLC tumor xenograft models. Since Anthracyclines exert antitumor activity based on their DNA damaging potential through topoisomerase II inhibition, we evaluated whether DNA damage signaling proteins and apoptosis-related proteins were affected by TAS-116 when given in combination with DOX. TAS-116 significantly reduced phosphorylation of CHK1, AKT and ERK1/2. In combination with these kinase inhibitors, SB 218078 significantly and MK-2206 moderately enhanced DOX-mediated apoptosis. Comparatively, TAS-116 enhanced apoptosis to a greater extent than SB 218078. Conclusion: TAS-116 showed antitumor activity against human SCLC tumor xenograft models alone and in combination with AMR. Our data suggest that TAS-116 enhanced the antitumor activity of Anthracyclines through the combined actions of abrogation of the DNA damage-induced G2/M checkpoint and the inhibition of a survival signal by CHK1 and AKT downregulation, respectively. These results suggest that TAS-116 could be a promising agent to treat extensive SCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C128. Citation Format: Hiromi Muraoka, Chihoko Yoshimura, Akihiro Hashimoto, Kenjiro Ito, Makoto Kitade, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi. TAS-116, an orally available HSP90α/β selective inhibitor, has potent antitumor activity in small cell lung cancer as a single agent and in combination with an Anthracycline Derivative, amrubicin. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C128.

Tadashi Suzuki – One of the best experts on this subject based on the ideXlab platform.

  • Chronic effects of a novel synthetic Anthracycline Derivative (SM-5887) on normal heart and doxorubicin-induced cardiomyopathy in beagle dogs
    Investigational New Drugs, 1998
    Co-Authors: Tomohiro Noda, Tomoyuki Watanabe, Akira Kohda, Shunji Hosokawa, Tadashi Suzuki

    Abstract:

    This study was designed to investigate the chronic cardiotoxic potential of SM-5887 and a possible deteriorating effect of SM-5887 on low-grade cardiotoxicity pre-induced by doxorubicin in beagle dogs. In the chronic treatment, beagle dogs of each sex were given intravenously once every 3 weeks, either a sublethal dose of doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg). The experiment was terminated 3 weeks after the ninth dosing. Animals which received over six courses of doxorubicin demonstrated the electrocardiogram (ECG) changes, decrease of blood pressure and high-grade histopathological cardiomyopathy, while animals which were terminally sacrificed after the SM-5887 administration did not show any changes in ECG, blood pressure and histopathological examinations. To examine a possibly deteriorating cardiotoxic effect of SM-5887, low-grade cardiomyopathy was induced in dogs by four courses of doxorubicin (1.5 mg/kg). Nine weeks after pre-treatment, dogs were given four courses of either doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg) once every 3 weeks. The low-grade cardiotoxic changes were enhanced by the additional doxorubicin treatment. On the contrary, the SM-5887 treatment did not progress the grade of cardiomyopathy. In conclusion, SM-5887 does not have any potential of chronic cardiotoxicity and deteriorating effect on doxorubicin-induced cardiotoxicity in dogs.

  • Cardiotoxicity of a new Anthracycline Derivative (SM-5887) following intravenous administration to rabbits: Comparative study with doxorubicin
    Investigational New Drugs, 1997
    Co-Authors: Tadashi Suzuki, Seiki Minamide, Tsutomu Iwasaki, Hirohisa Yamamoto, Hiroshi Kanda

    Abstract:

    The degree of cardiotoxicity of SM-5887 compared with that of doxorubicin was investigated in rabbits. Two experimental groups were administered high and low doses of SM-5887, respectively. One group was administered doxorubicin and another group was administered the vehicle only were prepared as positive and negative controls, respectively. Drugs were intravenously administered 3 times a week for 8 weeks. At terminus, electrocardiograms were recorded under anesthesia. The blood was collected for haematology and blood biochemistry analyses. Myocardial tissue damage was evaluated using light and electron microscopy. In the electrocardiogram study, prolongation of QTc interval and ST-T change were observed in rabbits administered SM-5887 and doxorubicin. Morphological studies showed that myocardial tissue damage in animals administered SM-5887 was comparable to that in the negative controls, and less than that observed in the positive controls. The general toxicological investigations uniformly indicated lower toxicity in the SM-5887 group than in the doxorubicin group at equivalent dosages. In total, considering the results of antitumor efficacy studies comparing SM-5887 with doxorubicin, these results indicate that the cardiotoxicity of SM-5887 is very slight, and that the general toxicity of SM-5887 is lower than that of doxorubicin.

  • cardiotoxicity of a new Anthracycline Derivative sm 5887 following intravenous administration to rabbits comparative study with doxorubicin
    Investigational New Drugs, 1997
    Co-Authors: Tadashi Suzuki, Seiki Minamide, Tsutomu Iwasaki, Hirohisa Yamamoto, Hiroshi Kanda

    Abstract:

    The degree of cardiotoxicity of SM-5887 compared with that of doxorubicin was investigated in rabbits.

Ryuichiro Nishigaki – One of the best experts on this subject based on the ideXlab platform.

  • Sonodynamically induced cell damage with 4′-O-tetrahydropyranyladriamycin, THP.
    Anticancer Research, 1999
    Co-Authors: Nagahiko Yumita, Masahiro Kaneuchi, Yukihiro Okano, Ryuichiro Nishigaki, Koshiro Umemura, Sayaka Umemura

    Abstract:

    Background. 4′-O-tetrahydropyranyladriamycin (THP) is a novel Anthracycline Derivative with cardiotoxicity significantly lower than ADM. In this study, the ultrasonically induced in vitro cell damaging effect of THP was investigated. Materials and methods. Sarcoma 180 cells suspended in air-saturated PBS were exposed to ultrasound for up to 60 s in the presence and absence of THP. The viability of the isolated cells was determined by staining of the cells with Trypan Blue dye. Results. The rate of inducing cell damage with ultrasound was doubled with 80 μM THP, while no cell damage was observed with THP alone. Conclusion. The enhancement of ultrasonically induced in vitro cell damage was demonstrated with THP. This enhancement was significantly inhibited by histidine, which may suggest a sonochemical mechanism.

  • Sonodynamically-induced cell damage with fluorinated Anthracycline Derivative, FAD104
    Cancer Letters, 1998
    Co-Authors: Nagahiko Yumita, Sayaka Umemura, Masahiro Kaneuchi, Yukihiro Okano, Koshiro Umemura, Naoki Magario, Midori Ishizaki, Keiko Shimizu, Yasuko Sano, Ryuichiro Nishigaki

    Abstract:

    The ultrasonically-induced in vitro cell damaging effect of fluorine-containing Anthracycline Derivative (FAD104) was investigated. Sarcoma 180 cells suspended in air-saturated PBS were exposed to ultrasound for up to 60 s in the presence and absence of FAD104. The rate of inducing cell damage with ultrasound was doubled with 80 μM FAD104, while no cell damage was observed with FAD104 alone. This enhancement was significantly inhibited by histidine, which may suggest a sonochemical mechanism.