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| 1.
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1. The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion.
Echizen, Kanae ; Oshima, Hiroko ; Nakayama, Mizuho ; Oshima, Masanobu ; 越前, 佳奈恵 ; 大島, 浩子 ; 中山, 瑞穂 ; 大島, 正伸
概要:
金沢大学新学術創成研究機構ナノ生命科学研究所<br />Accumulating evidence has indicated that the inflammatory response is important for tumor pr
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omotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF-α signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-β signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the “cancer-induced inflammation” mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE2 and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of-function mutations. © 2018 Elsevier Ltd.<br />Embargo Period 12 months
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山田, 外史
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Cancer is the most deadly disease in the world today. There is a variety of different treatment methods for cancer, incl
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uding radiotherapy and chemotherapy with anticancer drugs that have been in use over a long period of time. Hyperthermia is one of the cancer treatment methods that utilizes the property that cancer cells are more sensitive to temperature than normal cells. The control of temperature is an important task in achieving success using this treatment method. This paper reports the development of a novel needle-type nanosensor based on the spin-valve giant magnetoresistive (SV-GMR) technique to measure the magnetic flux density inside the body via pricking the needle. The sensor has been fabricated. The modeling and experimental results of flux density measurement have been reported. From the information of flux density, the temperature rise can be estimated to permit the delivery of controlled heating to precisely defined locations in controlled hyperthermia cancer treatment. The actual experiment with human is under investigation. © 2007, IEEE. All rights reserved.<br />Proceedings of the 1997 2nd International Conference on Power Electronics and Drive Systems, PEDS. Part 2 (of 2); Singapore, Singapore; ; 26 May 1997 through 29 May 1997; Code 47014
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| 3.
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Kitahara, Masaaki ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Mukaida, Naofumi ; Matsushima, Kouji ; Kaneko, Shuichi
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Background & aims Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy d
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epends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC. Methods We studied immunological data from 14 HCC patients. The DC preparation and the surface markers were assessed by flow cytometric analysis. Four different additional activation stimuli (Method I, medium alone; Method II, with OK-432; Method III, with IL-1β + IL-6 + TNF-α; Method IV, with IL-1β + IL-6 + TNF-α + PGE2) were tested and the functions of DCs were confirmed by examination of the ability of phagocytosis, cytokine production and allogeneic mixed lymphocyte reaction (MLR). Results The numbers of DCs induced and their cytokine production ability were not different between healthy controls and HCC patients. T-cell stimulatory activity of DCs in MLR was significantly lower in HCC patients than in healthy controls. The maturation of DCs with OK-432 boosted production of cytokines and chemokines, such as IL-2, IL-12p70, IFN-γ, TNF-α, IL-13 and MIP1α, and restored T-cell stimulatory activity of DCs in MLR. Conclusions The clinically approved compound OK-432 is a candidate for highly immunocompetent DC preparation and may be considered as a key drug for immunotherapy of HCV-related HCC patients. © 2014 Published by Elsevier B.V.
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Ogawa, Kazuma ; Kanbara, Hiroya ; Shiba, Kazuhiro ; Kitamura, Yoji ; Kozaka, Takashi ; Kiwada, Tatsuo ; Odani, Akira ; 小川, 数馬 ; 柴, 和弘 ; 北村, 暘二 ; 小阪, 孝史 ; 小谷, 明
概要:
金沢大学疾患モデル総合研究センター<br />BackgroundSigma receptors are highly expressed in human tumors and should be appropriate targets
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for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-p IV), with a high affinity for sigma receptors and prepared radioiodinated (+)-p IV. As a result, (+)-[125I]p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).Methods(+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]p IV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice.ResultsThe hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]p IV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]p IV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]p IV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]p IV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH.ConclusionsThe results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.
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Ogiwara, Shimpachiro ; Ikezawa, Yoko
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金沢大学大学院医学系研究科<br />PURPOSE: To demonstrate attitudes of health science students towards clients with cancer (ATC). The o
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bjective was three-fold: 1) to describe health science students' ATC, 2) to compare ATC amongst health science students according to their professional discipline, academic seniority and gender, 3) to note whether their ATC differed according to: a) their experience with cancer clients during clinical placement; and/or b) their acquired perception through their class-work of the need for psychological support for cancer clients. RELEVANCE: To show how important a student's prior classroom instruction and positive experience in clinical placement is to the establishment of an empathic attitude to clients with cancer. PARTICIPANTS: A total of 860 students participated from five professional disciplines of the School of Health Sciences at the University of Kanazawa, Japan. Five hundred and sixty-eight responded appropriately with the rate of response being 66 per cent. METHOD: The ATC scale consisted of 30 statements with six responses (+3, +2, +1, -1, -2, -3) for each statement. Two additional questions were provided on the questionnaire: a) whether or not a need for psychological support for such clients was perceived necessary as was instructed through their class-work; and b) students' experience with cancer clients during clinical placements. ANALYSIS: Descriptive analysis of student demographics, the Fisher's PLSD post-hoc test followed by multiple comparisons and the Mann-Whitney U test to determine any statistically significant difference in the ATC scores. RESULTS: Student nurses scored significantly high on the ATC scale, followed by laboratory science, physiotherapy, radiological technology and occupational therapy students. It was also found that all fourth year students scored significantly high on the ATC scale. The student nurses showed that they dealt with significantly large numbers of cancer clients during their clinical placements. The students who were affirmative to the two additional questions were found to have significantly higher ATC scores than those who were negative. CONCLUSION: Senior students' ATC was found to be more positive. Student nurses' approach to cancer clients was on a more person-to-person basis. Having experience alone with cancer clients was not sufficient to promote a positive ATC, but additional structured classroom instruction was found to play a necessary role in ATC.
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Mizukoshi, Eishiro ; Yamashita, Tatsuya ; Arai, Kuniaki ; Terashima, Takeshi ; Kitahara, Masaaki ; Nakagawa, Hidetoshi ; Iida, Noriho ; Fushimi, Kazumi ; Kaneko, Shuichi
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Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients
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with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC. © 2016 Springer-Verlag Berlin Heidelberg
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| 7.
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佐々木, 琢磨 ; Sasaki, Takuma
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金沢大学がん研究所<br />1.水溶媒中でミセルを形成するように胆汁酸を脱離基としたDACHPのミセル形成型白金錯体を合成し,その抗腫瘍活性を検討した. これられ錯体は全身投与可能な脂溶性錯体であり, マウス白血病L1210やマウス悪性黒
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色腫瘍B16メラノーマに対して,in vivoで著明な効果を示した. 脱離基分子上の水酸基の数,位置,配置が油層への溶解度,ミラル形成,抗腫瘍活性等に大きく影響を与えることを明らかにした.2.2′ーdeoxyー2′ーmethylideue cytidine(DMDC) の抗腫瘍活性を更に検討した. その結果, マウス白血病以外にヒト由未白血病細胞やヒト由未カルチノーマに対しても効果が見いだされ, DMDCが白血病のみならずヒト固型腫瘍にも有効であることが分った. 又, このDMDCは鶏卵法でもヒト肺癌に制癌効果を示した. 作用機作の解明を含めた広範な前臨床実験を目下実施中である.3.1,4ーbutanediol diー2,2,2ーtrifluoraethanesulfonate(BFS) と1,4ーbutanedioldiisethionate(BIT)を用いて,chronic myeloid leukemia(CML)に対する治療薬としての特性を既知制癌剤のbusulfanと比較検討した. その結果,busulfanは骨髓抑制以外の致死的毒作用を有し,しかもmgeloid系への選択毒性が,BFS,BITに比べて小さい事が判明した. 從って,BFS及びBITは,毒性面からも,またmyeloid選択毒性面から見てもbusulfanに優るCML治療薬となる可能性が強く示唆された.4.臨床応用可能な分化誘導物質をめざして,多数の新規核酸関連合成化合物を検討の結果,2,4ーdiethylー7,7,8,8ーtetramethylーcisー2,4ーdiazabicyclo〔4.2,0〕Octaneー3,5ーdioneがヒト前髓球性白血病細胞(HLー60)に対して強い分化誘導効果と増殖抑制効果を示すことを見出した. また,この新規分化誘導物質に,抗白血病剤(daunomycin)やビタミンA誘導体と併用すると,相乘的に作用が増強されることを見出した.<br />研究課題/領域番号:62010033, 研究期間(年度):1986 – 1987<br />出典：「新しい合成制癌剤の研究」研究成果報告書 課題番号62010033（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-62010033/)を加工して作成
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佐々木, 琢磨 ; Sasaki, Takuma
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金沢大学がん研究所<br />前年度に引続き2'ーdeoxycytidineの2'ーarabino位への置換基の導入を検討し、2'ーazido体(Cytarazid)の簡便、大量合成法を確立すると共に2'ーシアノ体(CNDAC)をラジカル反
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応を用いて新たに合成した。種々のヒト固型腫瘍由来細胞に対しCytarazid及びCNDACはともに強い増殖抑制効果を示した。また、podophyllotoxin型リグナン類の合成をDielsーAlder反応を用いて合成し、強い抗腫瘍活性を有する化合物を得ることができた。ブレオマイシンの細胞毒性は、ポリアクリル酸と撹拌すると増大するが、この時の細胞死は未知の致死機構によるものと考えられ、休止期細胞や耐性細胞にも同等に作用することを見出した。白金錯体を酸性多糖に結合させた高分子マトリックス型錯体を合成し、それらがB16ーF10メラノ-マの肺転移を抑制することを見出した。酸化還元代謝調節能を有するフラビンや5ーデアザフラビンの誘導体を合成した。これらの中でもNO_2基やCOOC_2H_5基を有するものが強い抗癌活性を示した。次に生元素の一つであるセレンを骨格内に導入した5ーデアザー10ーセレナフラビンを合成し、この化合物もかなり強い抗癌活性を有することを見出した。一方、ヒト腫瘍に対する簡便で能率の良い転移治療モデルとして、鶏卵胎児の転移多発臓器のおけるヒト腫瘍の微小転移巣に含まれるヒト腫瘍細胞の特定遺伝子をPolymerase Chain Reaction法により定量的に検出する我々独自の方法を用いて、転移抑制及び治療に有効な物質をスクリ-ニングした。その結果、本研究班で合成したDMDC(2'ーdeoxyー2'ーmethylidenecytidine)とCNDACがヒト線維肉腫HT1080の肝・肺の転移巣を顕著に抑制することがわかった。選択性の高いプロテインキナ-ゼ作用薬を得るために新しくデザインされたイソキノリン誘導体の細胞周期及び制癌剤多剤耐性に及ぼす影響を検討した結果、in vitroではあるが、P388/ADRの耐性解除作用の強い物質を見出した。<br />研究課題/領域番号:02151021, 研究期間(年度):1990<br />出典：「休止期細胞の動員と転移抑制効果を有する新合成制癌剤の探索」研究成果報告書 課題番号02151021（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-02151021/）を加工して作成
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服部, 絢一 ; Hattori, Kenichi
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金沢大学医学部<br />化学・X線・外科療法など集学的な癌根絶法と自家骨髄移植法の組合せで癌を治すことを研究目的として、次の研究成果が挙げられた。1.基礎的研究:移植用骨髄中に混在する癌細胞の除去法について(1)モノクローナル(モノ)抗体
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と補体の in vitro処理法 common ALL に対するJ-2、-5、BA-1、-2、-3(以上市販)、横山製NU-N2、愛知がんセンター製NL-1、-22、HL-47が試用に供され、T-ALLに対する山田製B-7、ATL-27などや横山製KOLT-2の実用性が検討されている。(2)4-hydroperoxycyclophosphamide(4HC)やimmunotoxinの in vitro処理法4-HCのCFU-Cへの影響が検討され、4-HCは分化型に比し末分化CFUへの抑制度は軽いことが明かにされた(三浦)。immunotoxinとして、モノ抗体・ricin結合体の適用性が検討された(永井、横山)。2. 臨床的研究:成人と小児の癌に対し行った成績を合せて述べる。固形癌91例、悪性リンパ腫19例中6例(=6/19)、ホジキン病1/2、肺小細胞癌1/12、神経芽腫2/11、脳腫瘍1/10、精巣癌4/8、ユーイング肉腫1/5、横紋筋肉腫1/5、骨肉腫2/4、鼻咽頭癌2/2、卵嚢癌、乳癌各1、合計23/91(25%)は移植後12〜66月間生存、うち悪性リンパ腫3例、精巣癌、鼻咽頭癌各1例は無治療で5年間健在で、本治療法が癌を治しうることを証明した。予じめ、モノ抗体と補体で処理した自家骨髄を移植した common ALL15例中3例は何れも16月間、無治療で寛解維持中、5例は1年未満ながら生存、観察中、残りの7例は再発または感染症で死亡し、再発防止に今一つの工夫を要することがわかった。まとめ 問題点である再発が、採取骨髄内の癌細胞の完全除去法と患者への徹底的な癌根絶法とで解決され、さらに本治療法に対する保険が全面的に適用されれば、本法により未分化癌を完治させる道が開かれるであろう。さらに目下開発中の高エネルギー粒子線が分化癌に効果があれば本法の適応は一段と拡大するであろう。<br />研究課題/領域番号:60010033, 研究期間(年度):1985<br />出典：「自己造血幹細胞の移植を応用する悪性腫瘍治療法の基礎的臨床的研究」研究成果報告書 課題番号60010033（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-60010033/)を加工して作成
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佐々木, 琢磨 ; Sasaki, Takuma
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金沢大学がん研究所<br />新しい化学構造ないし作用機序をもつ新しい合成制癌剤の開発を目指して、主に複素環化合物類の化学合成を行い、それら新規合成化合物の分化誘導活性と鶏卵法やヌードマウスを用いてヒト癌を含めた抗癌活性の検討を行った。1.
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既知制癌剤AraC と5FUの療法の性質を兼ね備えた新規化合物2'-メチリデンシチジンが顕著な抗白血病作用をもつことは前年度に報告した。今年度はこの物質の制癌効果を更に検討した結果:(1)静脈内及び経口投与でも有効である(2)AraCや5FUとは異なりP36(ヒトメラノーマ)にも有効である(3)Lewis 肺癌、M5076肉腫に対しても顕著な効果を示す(4)マウスでの骨髄毒性は、AraCに比して弱いこと等が明らかになり、ヒト固型腫瘍にも有効な新規制癌剤として極めて有望であることが確認された。2.新たにイミダゾールヌクレオシド類を合成し、その制癌活性を検討中であるが、invivoの実験系で腫瘍に対する選択性が極めて高く且つ毒性の低い物質であることが確認され、今までに報告されていないタイプの新規制癌剤として期待される。3.チロシンキナーゼ阻害剤であるハービマイシンAによるヒト骨髄性白血病細胞(K562)の分化誘導と増殖抑制効果を詳細に検討の結果、癌遺伝子産物の活性を特異的に抑制する薬剤は、分化誘導を介して制癌効果を発揮することが明らかになった。この新知見は、今後の新規合成制癌剤開発の重要な指針となるものと考えられる。4.新たに合成したフツ素あるいは水酸基を有する2種類のブスルファン誘導体(BFSおよびBIT)はいずれもブスルファンに比べて有意に坦癌動物に対する延命効果が優れており且つ動物に対する致死効果が小さい。これら誘導体は、chromic myeloid leukemia治療薬として、ブスルファンに勝る効果が期待される。<br />研究課題/領域番号:63010031, 研究期間(年度):1988<br />出典：「新しい合成制癌剤の開発」研究成果報告書 課題番号63010031（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-63010031/)を加工して作成
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