転移性ならびに深達性ヒト悪性黒色腫の選択的熱中性子捕捉療法の樹立

1993 年度 実績報告書

• 研究課題/領域番号: 05557044
• 研究機関: 神戸大学
• 研究代表者: 三嶋 豊 神戸大学, 医学部, 名誉教授 (10073743)
• 研究分担者: 平塚 純一 川崎医科大学, 講師 (30192298) ; 福田 寛 東北大学, 加齢医学研究所, 教授 (30125645) ; 吉野 和夫 信州大学, 理学部, 助手 (70143964) ; 古林 徹 京都大学, 原子炉実験所, 講師 (90089136) ; 市橋 正光 神戸大学, 医学部, 教授 (00030867)
• キーワード: 悪性黒色腫 / 熱中性子捕捉療法 / ポジトロンCT

研究概要

1.顔面発生の悪性黒子型黒色腫1例、単回照射で全治。肢端黒子型黒色腫1例を照射、腫瘍の著明退縮を認めたが全治に至らず。3.5月後第2回照射、観察中。経過順調。2.眼の黒色腫2例に^<10>B-BPA投与後、剔出組織の^<10>B濃度(ppm)測定。毛様体部腫瘍10.4と17.7 強膜6.6と7.7 血中5.3と5.2。眼黒色腫治療可能を示唆。3.1.記載患者の照射中および後の全身管理施行。経過順調。4.在来の中性子経路から黒鉛層を撤去、ビスマス面〜患者照射面 距離を延長、中性子の平行成分を増し、深部熱中性子束を高めた。93年6月以降実用。5.治療照射時に於ける中性子・体内元素間の反応分率分布と体内挿入金線の放射化量分布との相関を検討、吸収線量評価の信頼性を向上。6.被曝線量の正確な評価法を検討していたが、武工大炉不調のため実験中断。7.m-,o-BPAの光学分割を試み、m-では高純度のD-,L-体を単離。o-では高純度品を得ず。新規p-BPA類似化合物の合成に努力中。未成功。8.次項記載^<10>B-BPA-(OH)_2の水溶性、毒性、黒色腫細胞B-16と正常細胞TIGへの取込みを^<10>B-BPAと比較。-(OH)_2の方が取込量は小で、(癌/正常)取込比は大。9.^<10>B-BPAとH_2N-CH(CH_2OH)_2を3段階反応で縮合し目的の^<10>B-BPA-(OH)_2を合成。似た手法でウラシル・カルボラン・ポリグリセロール連結体も合成。10.症例から導いた次の近似値、即ち、投与^<10>B濃度比は腫瘍/血3〜4,皮膚/血1.3〜1.5;黒色腫根治線量25,皮膚耐容線量18RBE-Gyに基き、最適照射量を皮膚^<10>B濃度から算定。目安として有用。11.1.記載症例のcollimationと線量測定実施。トラック法実験はトラック分布と組織切片の対応に疑点残存。12.Glioblastoma 1症例に^<18>F-^<10>B-BPAと^<10>B-BPA(1g)を投与、PETで^<10>B濃度を求めた。腫内2.74,正常皮膚0.78ppm。13.Gadolinium錯体(Gd)含・不含のEhrlich腹水細胞をマウス皮下注、中性子照射。含有群に増殖抑制確認。家兎両肢にVX-2腫瘍移植、一肢からGd注入しつつ両肢照射。注入側に増殖の抑制。

研究成果

• [文献書誌] Mishima,Y.: "The diagnosis and treatment of malignant melanoma with special reference to neutron capture therapy." Melanoma Research. 3. 225-226 (1993)
• [文献書誌] Mishima,Y.: "In vivo diagnosis of human malignant melanoma using specific melanoma-seeking ^<18>F-compound with positron emission tomography." Kyoto University Research Reactor Institute-Technical Report(KURRI-TR). 374. 1-10 (1993)
• [文献書誌] 三嶋豊: "悪性黒色腫とその前癌症-最新治療概念と今後の展望-。" 新潟医学会雑誌. 107. 430-437 (1993)
• [文献書誌] Hatanaka,H.: "Improved bioavailability of para-boronophenylalanine by cyclodextrin complexation." J.of Pharmaceutical Sciences. 82. 1054-1057 (1993)
• [文献書誌] Mishima,Y.: "Neutron capture therapy of human malignant melanoma." KURRI Progress Report 1992(ISSN 0919-1038). 314-315 (1993)
• [文献書誌] Ichihashi,M.: "Studies on selective thermal neutron capture therapy of malignant melanoma-Determination of ^<10>B content by prompt γ-ray spectrometry-." KURRI Progress Report 1992(ISSN 0919-1038). 300-301 (1993)
• [文献書誌] Ichihashi,M.: "Studies on selective thermal neutron capture therapy of malignant melanoma-Evaluation of lethal effect of BNCT in vitro and in vivo-." KURRI Progress Report 1992(ISSN 0919-1038). 302-303 (1993)
• [文献書誌] 桜井良憲: "ハイパー熱中性子の中性子捕捉療法への利用の可能性。" 京都大学原子炉実験所第28回学術講演会報文集. 177-186 (1994)
• [文献書誌] 古林徹: "KUR重水熱中性子設備改造に関する原子炉物理工学面からの設計検討" 京都大学原子炉実験所第28回学術講演会報文集. 167-176 (1994)
• [文献書誌] Sakurai,Y.: "Feasibility study on neutron energy spectrum shifter in the KUR heavy water facility for neutron capture therapy." Annu.Rep.Res.Reactor Inst.Kyoto Univ.26. 8-25 (1993)
• [文献書誌] Sakurai,Y.: "A study on the utilization of hyper-thermal neutrons for neutron capture therapy." Annu.Rep.Res.Reactor Inst.Kyoto Univ.26. 26-33 (1993)
• [文献書誌] Kobayashi,T.: "A feasibility study on the neutron energy spctrum shift in the KUR heavy water facility mainly from the viewpoint of neutron capture therapy." Proc.4th Asian Symposium on Research Reactor(ASRR)Beijin China. 216-223 (1993)
• [文献書誌] Sakurai,Y.: "A feasibility study on the hyper-thermal neutron irradiation field for neutron capture therapy." Proc.4th Asian Symposium on Research Reactor(ASRR)Beijin China. 208-215 (1993)
• [文献書誌] 桜井良憲: "中性子捕捉療法における生体表面近傍での熱中性子線量測定およびその評価並びに生体深部での熱中性子線量分布の改善に関する研究。" KURRI-TR. 374. 119-138 (1993)
• [文献書誌] 高橋宏明: "o-およびm-ボロノフェニルアラニンの合成と光学分割。" KURRI-TR. 382. 29-32 (1993)
• [文献書誌] 吉野和夫: "p-ボロノフェニルアラニンとメラニン代謝前駆体L・ドーパとの錯形成および同錯体の酸化反応-p-ボロノフェニルアラニンによる悪性黒色腫への^<10>Bの集積、減衰機構の化学的考察-。" KURRI-TR. 382. 33-38 (1993)
• [文献書誌] 根本尚夫: "A new water-soluble p-boronophenylalanine for boron neutron capture therapy." Chem.Lett.465-468 (1993)
• [文献書誌] 福田寛: "癌の熱中性子捕捉治療。" 癌と科学療法誌. 21 (in press). (1994)
• [文献書誌] Fukuda,H.: "Optimization of neutron fluence and timing of irradiation for the treatment of malignant melanoma by boron neutron capture therapy using ^<10>B-paraboronophenylalanine." KURRI-TR.378. 212-220 (1993)
• [文献書誌] Akine,Y.: "Electron-equivalent dose for the effect of gadolinium neutron capture therapy on the growth of subcutaneously-inoculated Ehrlich tumor cells in mice." Jpn.J.Clin.Oncol.23. 145-148 (1993)
• [文献書誌] Akine,Y.: "Suppression of rabbit VX-2 subcutaneous tumor growth by gadolinium neutron capture therapy." Jpn.J.Cancer Res.84. 841-843 (1993)
• [文献書誌] Fukumori,Y.: "Design and preparation of ethyl cellulose microcapsules of gadopentetate dimeglumine for neutron capture therapy using wurster process." Chem.Pharm.Bull.41. 1144-1148 (1993)
• [文献書誌] 景平克志: "ガドリニウム中性子捕捉療法における線量評価。" 京都大学原子炉実験所第28回学術講演会報文集. 187-196 (1994)
• [文献書誌] Mishima,Y.: "“Dermatology:Progress and Perspectives",Proc.of the 18th World Congress of Dermatology(eds.Burgdorf,WHC.et al.)(Treatment of metastatic melanoma by neutron capture therapy.)" The Parthenon Pub.Group Ltd.,Lancs.,U.K., 1282 (1993)
• [文献書誌] 三嶋豊: "腫瘍鑑別診断アトラス 色素性腫瘍(皮膚の黒色腫-悪性黒色腫の発生-)(中島孝,石原和之編)" 文光堂,東京, 219 (1993)
• [文献書誌] Mishima,Y.: "“Advances in Neutron Capture Therapy",Proc.5th Int'l.Symp.on Neutron Capture Therapy for Cancer(eds.Soloway,AH,et al) (Selective melanoma thermal neutron capture therapy for lymph node metastases.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Honda,C.: "ibid.(Deuteriation trials for neutron capture therapy of deep-seated melanoma lesions.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Ichihashi,M.: "ibid.(Thermal neutron capture therapy using ^<10>B_1-BPA:Inducement of marked lethal effect on melanoma cells irrespective of X-ray sensitivity.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Yoshino,K.: "ibid.(Capture of p-boronophenylalanine by melanin-related compounds:Complex formation of p-boronophenylalanine with L-dopa.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Yoshino,K.: "ibid.(Proposed mechanism of capture and release of p-boronophenylalanine through melanoma cells:Chemical behaviour of p-boronophenylalanine-fructose complex in L-dopa solution.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Yoshino,K.: "ibid.(Determination of p-boronophenylalanine in biological tissues with high performance liquid chromatography.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Kakihana,H.: "ibid.(Relation between structures of p-boronophenylalanine related compounds and their usefulness for boron neutron capture therapy.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Yoshino,K.: "“Advances in Neutron Capture Therapy",Proc.5th Int'l.Symp.on Neutron Capture Therapy for Cancer(eds.Soloway,AH,et al)(Synthesis of o- and m-boronophenylalanine.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Akine,Y.: "ibid.(Gadolinium neutron capture therapy:Growth suppression of Ehrlich ascites and subcutaneously-implanted tumor cells in mice.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Tokuuye,K.: "ibid.(Biological dosimetry for gadolinium neutron capture reaction.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Kobayashi,T.: "ibid.(Analytical dose calculation in cell nucleus fromspherical ^<10>B containing region for neutron capture therapy.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Kobayashi,T.: "ibid.(Study on remodeling of the heavy water facility of the Kyoto University Reactor from the concept of energy spectrum control for neutron capture therapy.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Sakurai,Y.: "ibid.(Improvement of thermal fluence at the deeper part in tissue for BNCT:Simulation calculation and pahntom experiment.)" Plenum Press,New York, 829 (1993)
• [文献書誌] Kanda,K.: "ibid.(Experiences of BNCT using the KUR.)" Plenum Press,New York, 829 (1993)