The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform

Hitoshi Hori - One of the best experts on this subject based on the ideXlab platform.

  • The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy
    International Journal of Hyperthermia, 2020
    Co-Authors: Shinichiro Masunaga, Yoshinori Sakurai, Minoru Suzuki, Akira Maruhashi, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose: To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40°C, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs.Materials and methods: TX-2100 is a hybrid compound that has both a Hypoxic Cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by γ-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with T...

  • the novel Hypoxic Cytotoxin tx 2098 has antitumor effect in pancreatic cancer possible mechanism through inhibiting vegf and hypoxia inducible factor 1α targeted gene expression
    Experimental Cell Research, 2012
    Co-Authors: Kotaro Miyake, Hideko Nagasawa, Hitoshi Hori, Masanori Nishioka, Satoru Imura, Erdenebulgan Batmunkh, Mitsuo Shimada
    Abstract:

    Abstract Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel Hypoxic Cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P

  • Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.
    Anticancer Research, 2010
    Co-Authors: Hitoshi Hori, Eiji Nakata
    Abstract:

    We describe herein for the first time our medicinal electronomics bricolage design of hypoxia- targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor Hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia- targeting drugs, antiangiogenic Hypoxic cell radiosensitizers, sugar-hybrid Hypoxic cell radiosensitizers, and hypoxia- targeting 10 B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic Hypoxic cell radiosensitizer TX-2036, a sugar-hybrid Hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate- 10 B)-Hypoxic Cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas. Most current cancer therapies target tumor cells directly. Recently, a newly emerging area of cancer or neoplastic therapeutics focuses instead on targeting cells of the tumor- specific environment or microenvironment (1). The Hypoxic tumor environment is now considered a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. For three decades, we have been concentrating much effort on the development of chemical modifiers of cancer treatment (2), including Hypoxic cell radiosensitizers, Hypoxic Cytotoxins, hypoxia-targeting antineoplastic drugs (3), and Gc protein-derived macrophage-activating factors (4, 5). We provide here a thorough review of our strategy and tactics for drug design as a medicinal electronomics bricolage. In particular, we review our current progress in the development of hypoxia-targeting drugs, such as antiangiogenic Hypoxic cell radiosensitizers, sugar-hybrid Hypoxic cell radiosensitizers, and hypoxia-targeting 10 B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore elucidation. We also present here our development of an in vivo developing chick embryo model to evaluate the radiosensitizing activity of compounds against solid neoplasms. We also describe our design and syntheses of new compounds that target Hypoxic-neoplastic cells by functioning as indoleamine 2.3-dioxygenase (IDO) inhibitors. We further show that our hypoxia-targeting boron neutron capture therapy (BNCT) agents are promising boron-10 carrier candidates for BNCT. Finally, we present here our concept of what we call 'boron tracedrugs' as a new drug class with broad potential and also as next-generation pharmaceutical drugs. Boron tracedrugs are designed to have persistent traceability anytime during their lifetime. The key structural feature of these drugs consists of having multiple boron atoms firmly embedded in their scaffold or skeleton located at a position that will have little or no influence on other functional group moiety or pharmacophores.

  • Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells
    Journal of Cancer Research and Clinical Oncology, 2007
    Co-Authors: Shinichiro Masunaga, Minoru Suzuki, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the Hypoxic Cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors. Methods Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or γ-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of γ-rays while alive or after tumor clamping to obtain Hypoxic fractions (HFs) in the tumors. Results One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to γ-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to γ-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells. Conclusions Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and γ-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.

  • Design of hypoxia-targeting drugs as new cancer chemotherapeutics.
    Biological & Pharmaceutical Bulletin, 2006
    Co-Authors: Hideko Nagasawa, Kenneth L. Kirk, Hitoshi Hori
    Abstract:

    The tumor microenvironment is now recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also helps define the potential for malignant progression and metastasis. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment. Furthermore, discovery of the hypoxia inducible factor 1α (HIF-1α) has led to a rapidly increasing understanding of the molecular mechanisms involved in tumor hypoxia. This in turn has led to the current extensive interest in the signal molecules related to tumor hypoxia as potential molecular targets for cancer therapeutics. In this paper we give an overview of recent advances in hypoxia research, including cancer treatments that target tumor hypoxia. Progress in the development of hypoxia-targeting drugs will be discussed, including antiangiogenic Hypoxic cell radiosensitizers and Hypoxic Cytotoxins, hypoxia targeting boron carriers and p53-inhibiting bifunctional radiosensitizers. We will also review our own recent research results in these areas. For example, we have found that certain of the 2-nitroimidazole radiosensitizers and heterocycle-N-oxide Hypoxic Cytotoxins we developed have antiangiogenic activity and antimetastatic activity. We propose that these activities are based on the inhibition of signal transduction mediated by HIF-1α. The anti-tumor activities of hypoxia response are considered to be cytostatic (tumor dormancy-inducing) effects in contrast to cytotoxic DNA damaging effects. The combinaiton of these cytostatic effects that are related to radiosensitization with the cytotoxic effects of radiation should improve the prognosis and QOL of patients receiving radiation and lead to an overall response to treatment. Based on these considerations, we developed the antiangiogenic Hypoxic cell radiosensitizers, TX-1877, TX-1898 and the Hypoxic Cytotoxin TX-402 that inhibits the HIF-1α pathway We will also discuss our research involved with the development of other drugs to exploit tumor hypoxia, including a hypoxia-targeting boron carrier for boron neutron capture therapy (BNCT) and a p53 inhibiting radiosensitizer.

Yuko Kinashi - One of the best experts on this subject based on the ideXlab platform.

  • The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy
    International Journal of Hyperthermia, 2020
    Co-Authors: Shinichiro Masunaga, Yoshinori Sakurai, Minoru Suzuki, Akira Maruhashi, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose: To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40°C, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs.Materials and methods: TX-2100 is a hybrid compound that has both a Hypoxic Cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by γ-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with T...

  • Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells
    Journal of Cancer Research and Clinical Oncology, 2007
    Co-Authors: Shinichiro Masunaga, Minoru Suzuki, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the Hypoxic Cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors. Methods Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or γ-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of γ-rays while alive or after tumor clamping to obtain Hypoxic fractions (HFs) in the tumors. Results One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to γ-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to γ-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells. Conclusions Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and γ-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.

  • Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells
    Journal of Cancer Research and Clinical Oncology, 2006
    Co-Authors: Shinichiro Masunaga, Minoru Suzuki, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the Hypoxic Cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors.

  • Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-^10B conjugates as^10B-carriers in boron neutron capture therapy
    Radiation Medicine, 2006
    Co-Authors: Shinichiro Masunaga, Yoshinori Sakurai, Minoru Suzuki, Akira Maruhashi, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Keiko Gotoh, Yuko Kinashi
    Abstract:

    Purpose To evaluate the usefulness of 5 new^10B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as^10B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402 and a clinically used^10B-carrier, sodium borocaptate-^10B (BSH). Materials and Methods The 5 new compounds were hybrid compounds that have both a Hypoxic Cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the^10B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor^10B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [=quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. Results ^10B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of^10B in tumors and maintaining a high enough^10B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with γ-rays not only on total cells but also on Q and Hypoxic tumor cells, which was not achieved by BSH. Conclusion A^10B-carrier that acts as a Hypoxic Cytotoxin on tumor cells as well as having the potential to keep^10B in tumors and sensitize tumor cells more markedly than conventional^10B-carriers, such as TX-2100, is a promising candidate for use in BNCT.

  • combination of the antivascular agent zd6126 with Hypoxic Cytotoxin treatment with reference to the effect on quiescent tumor cells and the dependency on p53 status of tumor cells
    Oncology Reports, 2005
    Co-Authors: Shinichiro Masunaga, Minoru Suzuki, Hideko Nagasawa, Hitoshi Hori, Ken Ohnishi, Akihisa Takahashi, Takeo Ohnishi, Kenji Nagata, Yuko Kinashi
    Abstract:

    : Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received a Hypoxic Cytotoxin, tirapazamine (TPZ) or TX-402, with or without a vascular targeting agent (VTA), ZD6126. Another group of mice given ZD6126 received a series of test doses of gamma-rays while alive or after tumor clamping to obtain Hypoxic fractions (HFs) in the tumors. After each treatment, the tumor cells were isolated and incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling [quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from the tumors that were not pretreated with BrdU. Both Hypoxic Cytotoxins showed significantly greater toxicity toward SAS/mp53 and Q than SAS/neo and total tumor cells, respectively. The sensitivity to TX-402 was significantly higher than that to TPZ in both total and Q tumor cells of both tumors. The significant enhancive effect by ZD6126 combined with each Hypoxic Cytotoxin was similar irrespective of p53 status, and slightly greater for total than Q cells probably because of a more marked increase in the size of the HFs in total than Q cells on the use of ZD6126 in both tumors, resulting in a reduction of the difference in the sensitivity to the Hypoxic Cytotoxin between total and Q cells. In the treatment of conventional cancer therapy-resistant Q tumor cells or p53-mutated tumor cells, the use of Hypoxic Cytotoxin was very promising either alone or when VTA was co-administered. TX-402 might be more promising than TPZ, although further study of the toxicity to normal tissue is needed.

Hideko Nagasawa - One of the best experts on this subject based on the ideXlab platform.

  • The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy
    International Journal of Hyperthermia, 2020
    Co-Authors: Shinichiro Masunaga, Yoshinori Sakurai, Minoru Suzuki, Akira Maruhashi, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose: To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40°C, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs.Materials and methods: TX-2100 is a hybrid compound that has both a Hypoxic Cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by γ-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with T...

  • the inhibitory effect of Hypoxic Cytotoxin on the expansion of cancer stem cells in ovarian cancer
    Biochemical and Biophysical Research Communications, 2015
    Co-Authors: Noriko Nozawasuzuki, Hideko Nagasawa, Ken Ohnishi, Kenichirou Morishige
    Abstract:

    Abstract While an increase in progression free survival time is seen when an angiogenesis inhibitor is used in the treatment of high-relapse rate ovarian cancer, it has little effect on overall survival. A possible cause of treatment-resistance to angiogenesis inhibitors is the growth of stem cells in a Hypoxic microenvironment built inside the tumor tissue by angiogenesis inhibition. In this study, we examined the possible suppression of stem cell and cancer stem cell (CSC) expansion by Hypoxic Cytotoxin, TX-402. TX-402, an analogue of tirapazamine, has been developed as a hypoxia selective prodrug with inhibitory effects of HIF-1 and angiogenesis. We considered TX-402 as a possible molecular-target drug candidate for ovarian cancer due to its inhibition of CSC expansion. In this study, we found that the expressions of HIF-1α and HIF-2α were increased under hypoxia in serous ovarian cancer cell lines. The expressions of HIF-1α and HIF-2α induced under hypoxia were repressed by TX-402 in a dose-dependent manner. Next, we investigated the effects of hypoxia on the expression levels of stem cell factors, Oct4, Nanog, Sox2 and Lin28, and showed that their expressions were induced by hypoxia. It was also observed that the expressions of putative ovarian cancer stem cell markers, CD133 and CD44 were induced under hypoxia. Furthermore, TX-402 was found to dose-dependently inhibit the expressions of CSC markers and stem cell factors. Oct4 expression was repressed by HIF-2α silencing, but not by HIF-1α silencing, indicating that TX-402 may repress the expression of Oct4 by inhibiting HIF-2α. We constructed CaOV3 spheroids as a 3-dimensional hypoxia model, in which the internal Hypoxic region contained CSC-like cells expressing Oct4. The internal Hypoxic region, which contained Oct4 expressing cells, disappeared following TX-402 treatment. In conclusion, hypoxia promoted the expansion of CSCs expressing CD133 and CD44 accompanied by an increase of stem cell factors. Its inhibition of hypoxia-induced CSC expansion makes TX-402 promising agent usable in combination for ovarian cancer therapy.

  • the novel Hypoxic Cytotoxin tx 2098 has antitumor effect in pancreatic cancer possible mechanism through inhibiting vegf and hypoxia inducible factor 1α targeted gene expression
    Experimental Cell Research, 2012
    Co-Authors: Kotaro Miyake, Hideko Nagasawa, Hitoshi Hori, Masanori Nishioka, Satoru Imura, Erdenebulgan Batmunkh, Mitsuo Shimada
    Abstract:

    Abstract Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel Hypoxic Cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P

  • Design of Novel Hypoxia-Targeting IDO Hybrid Inhibitors Conjugated with an Unsubstituted L-TRP as an IDO Affinity Moiety
    Advances in Experimental Medicine and Biology, 2009
    Co-Authors: Hitomi Nakashima, Hideko Nagasawa, Kazuhiro Ikkyu, Kouichiro Nakashima, Keiichiro Sano, Eiji Nakata, Hiroshi Sugimoto, Yoshitsugu Shiro, Yoshinori Nakagawa
    Abstract:

    We presented here design, syntheses and inhibitory activities of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a Hypoxic Cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2.

  • Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells
    Journal of Cancer Research and Clinical Oncology, 2007
    Co-Authors: Shinichiro Masunaga, Minoru Suzuki, Hideko Nagasawa, Hitoshi Hori, Kenji Nagata, Yuko Kinashi
    Abstract:

    Purpose The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the Hypoxic Cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors. Methods Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or γ-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of γ-rays while alive or after tumor clamping to obtain Hypoxic fractions (HFs) in the tumors. Results One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to γ-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to γ-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells. Conclusions Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and γ-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.

Shinichiro Masunaga - One of the best experts on this subject based on the ideXlab platform.

Andrew I Minchinton - One of the best experts on this subject based on the ideXlab platform.

  • targeting the tumour vasculature exploitation of low oxygenation and sensitivity to nos inhibition by treatment with a Hypoxic Cytotoxin
    PLOS ONE, 2013
    Co-Authors: Jennifer H E Baker, Alastair H Kyle, Kirsten L Bartels, Stephen P Methot, Erin J Flanagan, Andrew Balbirnie, Jordan Cran, Andrew I Minchinton
    Abstract:

    Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by Hypoxic Cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a Hypoxic Cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels.

  • detecting vascular targeting effects of the Hypoxic Cytotoxin tirapazamine in tumor xenografts using magnetic resonance imaging
    International Journal of Radiation Oncology Biology Physics, 2009
    Co-Authors: Lauren J Bains, Andrew I Minchinton, Jennifer H E Baker, Alastair H Kyle, Stefan A Reinsberg
    Abstract:

    Purpose: To determine whether vascular-targeting effects can be detected in vivo using magnetic resonance imaging (MRI). Methods and Materials: MR images of HCT-116 xenograft-bearing mice were acquired at 7 Tesla before and 24 hours after intraperitoneal injections of tirapazamine. Quantitative dynamic contrast-enhanced MRI analyses were performed to evaluate changes in tumor perfusion using two biomarkers: the volume transfer constant (K{sup trans}) and the initial area under the concentration-time curve (IAUC). We used novel implanted fiducial markers to obtain cryosections that corresponded to MR image planes from excised tumors; quantitative immunohistochemical mapping of tumor vasculature, perfusion, and necrosis enabled correlative analysis between these and MR images. Results: Conventional histological analysis showed lower vascular perfusion or greater amounts of necrosis in the central regions of five of eight tirapazamine-treated tumors, with three treated tumors showing no vascular dysfunction response. MRI data reflected this result, and a striking decrease in both K{sup trans} and IAUC values was seen with the responsive tumors. Retrospective evaluation of pretreatment MRI parameters revealed that those tumors that did not respond to the vascular-targeting effects of tirapazamine had significantly higher pretreatment K{sup trans} and IAUC values. Conclusions: MRI-derived parameter maps showed good agreement with histological tumor mapping. MRImore » was found to be an effective tool for noninvasively monitoring and predicting tirapazamine-mediated central vascular dysfunction.« less

  • Exploring vascular dysfunction caused by tirapazamine.
    Microvascular Research, 2007
    Co-Authors: Lynsey A. Huxham, Alastair H Kyle, Jennifer H E Baker, Krista L. Mcnicol, Andrew I Minchinton
    Abstract:

    Abstract We have previously reported that the Hypoxic Cytotoxin tirapazamine causes central vascular dysfunction in HCT-116 xenografts. Here we further extend this finding to SiHa xenografts and SCCVII murine tumors. Within 1 day after treatment with tirapazamine both tumor types develop areas of non-perfused tissue in central regions of tumors. To explore the mechanism by which the Hypoxic Cytotoxin tirapazamine causes vascular dysfunction we altered the blood oxygen content with carbogen (95% O 2 and 5% CO 2 ) breathing in tumor bearing mice. Carbogen treatment was able to decrease the number of tumors responding to tirapazamine but was not able to eradicate the vascular dysfunction completely. In complementary in vitro studies, immunohistochemical staining of tirapazamine-treated endothelial cells indicated that, unlike the vascular targeting agent (VTA) combretastatin-A-4-phosphate, the vascular effects caused by tirapazamine are not due to microtubule disruption. Another possible mechanism of action for tirapazamine could involve its ability to inhibit nitric oxide synthase (NOS). Studies combining other vascular targeting agents (VTAs) such as the combretastatins have shown a potentiation of vascular disruption in tumors when combined with NOS inhibitors, possibly due to vessel constriction from decreased nitric oxide (NO) levels. We propose the theory that vascular dysfunction caused by tirapazamine may be via NOS inhibition. In support of this hypothesis preliminary experiments showed NOS inhibition with l -NNA ( N -omega-nitro- l -arginine) increases tumor necrosis, 1 day after administration, in our HCT-116 tumor model.

  • Tirapazamine causes vascular dysfunction in HCT-116 tumour xenografts
    Radiotherapy and Oncology, 2006
    Co-Authors: Lynsey A. Huxham, Alastair H Kyle, Jennifer H E Baker, Krista L. Mcnicol, Andrew I Minchinton
    Abstract:

    Abstract Background and purpose Tirapazamine is a Hypoxic Cytotoxin currently undergoing Phase II/III clinical evaluation in combination with radiation and chemotherapeutics for the treatment of non-hematological cancers. Tissue penetration studies using multicellular models have suggested that tirapazamine exposure may be limited to cells close to blood vessels. However, animal studies show tirapazamine enhances the anti-tumour activity of radiation and chemotherapy and clinical studies with tirapazamine, so far, are promising. To investigate this apparent paradox we examined the microregional effects of tirapazamine in vivo by mapping drug effects with respect to the position of blood vessels in tumour cryosections. Patients and methods Tirapazamine was administered i.p. to mice bearing HCT-116 tumours, which were excised at various times after treatment. Images of multiple-stained cryosections were overlaid to provide microregional information on the relative position of proliferating cells, hypoxia, perfusion and vasculature. Results We observed extensive and permanent vascular dysfunction in a large proportion of tumours from mice treated with tirapazamine. In the affected tumours, blood flow ceased in the centrally located tumour vessels, leaving a rim of functional vessels around the periphery of the tumour. This vascular dysfunction commenced within 24 h after tirapazamine administration and the areas affected appeared to be replaced by necrosis over the following 24–48 h. Conclusions Because the majority of Hypoxic cells are located in the center of tumours we propose that the activity of tirapazamine in vivo may be related to its effects on tumour vasculature and that its activity against Hypoxic cells located distal to functional blood vessels may not be as important as previously believed.

  • the Hypoxic Cytotoxin sr 4233 increases the effectiveness of radioimmunotherapy in mice with human non hodgkin s lymphoma xenografts
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Richard B Wilder, Judeth K Mcgann, W Sutherland, Edmund K Waller, Andrew I Minchinton, Michael L Goris, Susan J Knox
    Abstract:

    Abstract Purpose: To determine if either the Hypoxic cell radiosensitizer etanidazole (SR 2508) or the Hypoxic Cytotoxin SR 4233 could improve the effectiveness of radioimmunotherapy. Methods and Materials: LC4 (an IgG, monoclonal antibody directed toward malignant T cells) and MB-1 (an irrelevant isotype-matched control antibody) were injected intraperitoneally into severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts in order to determine the distribution of the antibodies in the tumors and normal tissues as a function of time. Computerized-pO 2 -histography was used to measure the median oxygen tension in the tumors. Tumor-bearing mice were treated with: (a) LC4; (b) 90 YLC4; (c) 90 YMB1; (d) whole body irradiation delivered via an external 137 CS source; (e) etanidazole and 90 YLC4; (f) SR 4233 and 90 YLC4; (g) etanidazole; and (h) SR 4233. An additional group of mice received no treatment and served as controls. A tumor growth delay assay was used to assess the effectiveness of the different treatment regimens. Results: LC4 accumulated in the tumors to a significantly greater extent than MB-1 ( p p = 0.001). 90 YLC4 produced greater tumor growth delay than LC4 alone (LC4 vs. 90 Y-LC4; p = 0.01); however, the Yttrium-90 caused neutropenia and weight loss. The 90 Y-labeled tumor-specific and non-specific antibodies both exerted greater tumor growth delay than externally delivered whole body irradiation ( p ≤ 0.03) due to preferential uptake of the antibodies in the tumors. Etanidazole and SR 4233 by themselves did not significantly inhibit the growth of the tumors. Etanidazole did not significantly enhance the tumor growth delay produced by 90 YLC4 ( 90 YLC4 vs etanidazole and 90 YLC4, p = 0.13). SR 4233, on the other hand, did enhance the tumor growth delay produced by 90 YLC4 ( 90 YLC4 vs. SR 4233 and 90 YLC4, p = 0.046). The neutropenia and weight loss caused by 90 YLC4 were exacerbated slightly ( Conclusions: A first generation Hypoxic Cytotoxin, SR 4233, was able to enhance the tumor growth delay produced by radioimmunotherapy in severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts.