ホウ素熱中性子捕捉療法の適応拡大に関する研究 副題:単クロ-ン抗体利用の ^<10>B集積,即発γ線による癌診断,L体単離による ^<10>BーBPAの薬効増強

1990 年度 実績報告書

• 研究課題/領域番号: 02151038
• 研究機関: 神戸大学
• 研究代表者: 三島 豊 神戸大学, 医学部, 教授 (10073743)
• 研究分担者: 井戸 達雄 東北大学, サイクロトロンラジオアイソトープセンター, 教授 (80134063) ; 玉置 憲一 東海大学, 医学部, 教授 (50055860) ; 吉野 和夫 信州大学, 理学部, 助手 (70143964) ; 奥村 勝彦 神戸大学, 医学部, 教授 (60025707) ; 神田 啓治 京都大学, 原子炉実験所, 助教授 (10027419)
• キーワード: 熱中性子捕捉療法 / 単クロ-ン抗体 / シクロデキストリン / 磁気共鳴画像

研究概要

1.新発売の米国製M_2・ ^<10>B_<12>H_<12>(M:Na,Cs)を原料とし, ^<10>B抗体作用の ^<10>B化剤を合成したが純度・収量低く実用不可。同原料の精製法を案出,実用可能品を得た。2.人工抗原GM3リポソ-ムをキラ-T細胞(CTL)に働かせ,GM3モル濃度5〜9%で抗メラノ-マCTLを得,抗体との関係に論及。3.I^<128>標識763.74T抗体のP22黒色腫細胞への顕著な集積を確認後,ビオチン化763.74Tと ^<10>Bーアビジンの複合体をP22に作用させ,第13項記載のICPーMS法で,1細胞当り2.6×10^8個の ^<10>B原子の集積を証明。4. ^<10>Bーdextran含有液中のHeLa細胞に原子炉照射しRBEを算出。 ^<60>Cor1.0に対し熱中性子1.5〜2.0, ^<10>B(n,α)^7Li反応5.5〜6.0。5.マウス黒色腫細胞のX線感受株,抵抗株(感受性差Do値で30cGy)とヒト同細胞の両株(差96cGy)を得た。6. ^<10>B薬物をハムスタ-・兎・マウスに投与,即発γ線法で ^<10>B体内濃度の時間変化を追跡。ヒト2症例の診断に同法を応用。7.300,700,1500mg/kgの ^<10>BーBPAをラットに28日間連続経口投与し,摂食・摂水量,体重,臓器重量,血液検査による亜急性毒性試験実施中。8. ^<10>BーBPAのcyclodextrin錯体,fructose錯体を黒色腫担癌ハムスタ-に経口投与。前者は後者に比し血中BPA濃度の時間積分値と腫内BPA濃度は大,胃腸間内BPA残存量は小。9.酵素法により光学純度100%に近いL体とD体を得た。高速液体クロマト法でL体とD体の完全分離に成功,本法は純度検定に好適。10.数種の抗GD2単クロ-ン抗体のうち,IgG3サブクラスはヒト黒色腫担癌ヌ-ドマウスの腫瘍増殖を顕著に抑制した。 ^<10>B化すれば本療法用に有望。11.黒色腫9症例の皮膚障害より ^<10>B(n,α)^7Li反応のRBEを2.0〜2.5と推定。ラット投与重水の磁気共鳴画像を得て,組織血流測定。12.BPAの ^<18>F標識物[Fー18]ーFBPAはヒト患者の脳転移黒色腫に集積し,画像明瞭。黒色腫担癌ハムスタ-でL体の腫内集積はDL体の2倍以上。13.第3項の分析試料1mlはP22細胞2×10^5個を含みIcpーMSによる ^<10>B量は0.885ng。上記 ^<10>B集積数は目標値1×10^9に今一歩。

研究成果

• [文献書誌] Honda,C.: "In situ detection of cutaneous melanoma by prompt gammaーray spectrometry using melanomaーseeking ^<10>Bーdopa analogue." Journal of Dermatological Science. 1. 23-32 (1990)
• [文献書誌] Ishiwata,K.: "4ーBoronoー[ ^<18>F]fluoroーD,Lーphenylalanine as a target compound for boron neutron capture therapy:Tumor imaging potential with positron emission tomography." Nuclear Medicine & Biology. (1991)
• [文献書誌] Harada,Y.: "Induction of mouse antiーmelanoma cytotoxic and suppressor T cells in vitro by an artificial antigen,GM3ーlactone." Japanese Journal of Cancer Research. 81. 383-387 (1990)
• [文献書誌] Ujeno,Y.: "Mathematical analysis of the survival of HeLa S3 cells following neutron capture radiation:Calculation of RBE by a linearーquadratic model." Annual Reports of the Research Reactor Institute,Kyoto University. 23. 91-96 (1990)
• [文献書誌] 吉野 和夫: "悪性黒色腫用 ^<10>B化合物ド-パボレ-トとpーボロノフェニルアラニンの化学的挙動と中性子捕捉療法" KURRIーTR (Kyoto University Research Reactor InstituteーTechnical Report). 335. 18-27 (1990)
• [文献書誌] Ishiwata,K.: "Synthesis and radiation dosimetry of 4ーboronoー2ー[ ^<18>F]fluoroーD,Lーphenylalanine:a target compound for PET and boron neutron capture therapy." Appl.Radiat.Isot.42. 325-328 (1991)
• [文献書誌] 市橋 正光: "悪性黒色腫の熱中性子捕捉療法" 臨床皮膚科. 44(5). 643-649 (1990)
• [文献書誌] Mishima,Y.: "CUTANEOUS MELANOMA BIOLOGY AND MANAGEMENT (New methods of treatment of melanoma)" Masson S.p.A.,Milano, 272 (1990)
• [文献書誌] Hayashibe,K.: "HUMAN MELANOMA:From Basic Research to Clinical Application (Role of melanosomal antigen in melanoma regression and depigmentation)" SpringerーVerlag,Berlin, 557 (1990)
• [文献書誌] Komura,A.: "Proc.of 4th International Symposium on Neutron Capture Therapy,Dec.4ー7,1990,Sydney (Thermal neutron capture therapy (NCT) using ^<10>Bーconjugated antimelanoma antibodies:Quantification of ^<10>B on cultured human melanoma cells)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Shiono,M.: "ibid.(In vivo cellular pharmacology on the selective affinity of ^<10>B_1ーBPA into malignant melanoma.)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Mishima,Y.: "Proc.of 14th International Pigment Cell Conference,Oct.31ーNov.4,1990,Kobe (New perspectives on melanomaーgenesis and its control)" MUNKSGAARD International Publishing Ltd., (1991)
• [文献書誌] Taniguchi,M.: "HUMAN MELANOMA:From Basic Research to Clinical Application (Crossーspecies melanoma antigen)" SpringerーVerlag,Berlin, 557 (1990)
• [文献書誌] Kurosu,A.: "BIOLOGICAL AGENTS IN THE TREATMENTOF CANCER,Proc.of International Conference on Biological Treatment of Melanoma and Other Cancers,Sept.4ー7,1990,Newcastle (Mouse melanoma antigens and autoreactive T cell responses.)" International Conference on Biological Treatment of Melanoma and Other Cancers, 537 (1990)
• [文献書誌] Utsumi,H.: "Proc.of 2nd International Neutron Therapy Workshop:Brachy and Boron Neutron Capture Therapy,May 25ー27,1990,Lexington (The radiation biology of boron neutron capture therapy.)" Harwood Academic Publishers GMBH, (1991)
• [文献書誌] Kanda,K.: "Proc.of 4th International Symposium on Neutron Capture Therapy,Dec.4ー7,1990,Sydney (Procedures for medical application of research reactors.)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Kanda,K.: "Proc.of 4th International Symposium on Neutron Capture Therapy,Dec.4ー7,1990,Sydney (Progress of physics study for boron neutron capture therapy) (in press)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Yoshino,K.: "ibid.(Complete separation of racemic pーboronophenylalanine by high performance liquid chromatography with crown etherーcoated reversedーphase packings.) (in press)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Kinoshita,Y.: "ibid.(Complex formation of phenylboronic acid derivatives with aldopentoses and oligoーsaccharides.) (in press)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Fukuda,H.: "ibid.(Tolerance limits of the normal tissue irradiated by a single treatment of BNCT.) (in press)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Ichihashi,M.: "ibid.(In vitro evaluation of ^<10>BーBPA for malignant melanoma at MOATAーjoint work between Japan and Australia BNCT Research Teams.) (in press)" Plenum Publishing Corporation,New York, (1991)
• [文献書誌] Ichihashi,M.: "Proc.of 14th International Pigment Cell Conference,Oct.31ーNov.4,1990 Kobe (In vitro radiobiological analysis on ^<10>BーLーBPA BNCT of malignant melanoma:Correlation of determined ^<10>Bーcontent and cell killing effect.) (in press)" MUNKSGAARD,International Publishing Ltd., (1991)