JPS635379B2 - - Google Patents
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- Publication number
- JPS635379B2 JPS635379B2 JP53082139A JP8213978A JPS635379B2 JP S635379 B2 JPS635379 B2 JP S635379B2 JP 53082139 A JP53082139 A JP 53082139A JP 8213978 A JP8213978 A JP 8213978A JP S635379 B2 JPS635379 B2 JP S635379B2
- Authority
- JP
- Japan
- Prior art keywords
- particles
- cancer
- cancer cells
- composition
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
【発明の詳細な説明】
本発明は生体組織内の癌治療用組成物に関す
る。特に本発明は正常細胞を傷なわずに癌細胞を
細胞内で死滅させる癌治療法に使用するための治
療用組成物に関する。
現在癌治療法には放射療法、化学療法、免疫療
法および外科手術の様な多数の方法がある。これ
らの方法および現在知られた方法のすべてに共通
な特徴はそれらが細胞外領域のものである、即ち
癌細胞に細胞外から殺す力又は媒質を応用して細
胞を攻げきし絶滅しようとするものである。
癌細胞の外膜は間に脂質層をもつ２蛋白質層か
ら成りそのかたい膜を浸透するのは困難な為この
細胞外方法は効果効率が小さいことが発見されて
いる。細胞外方法において細胞膜による細胞の防
護に打勝つことに大きな意味があつても、癌細胞
攻げきは普通細胞にかなりの損傷を与え患者に重
大な悪影響を起す様な強力なものでなければなら
ない。この悪影響はこの治療の効果と効用をかな
り限定することが発見されている。
安全有効な癌治療法は永い間研究目標であつた
のである。癌細胞の絶滅に成功する方法は結局癌
細胞に選択的であり普通の細胞に回復し難い損傷
を与えないものでなければならない。結局癌治療
法は癌細胞を普通細胞と選択的に区別し普通細胞
に影響なく癌細胞を選択的に弱める又は殺す必要
がある。
癌細胞と普通細胞の間にある物理的差違のある
ことは知られている。１主要物理的差違は癌細胞
と普通細胞の間の温度差違特性にある。癌細胞は
代謝作用速度の大きい為普通細胞に比べて基礎温
度が高い。生体細胞において癌細胞の通常温度は
37.5℃と知られているが、普通細胞のそれは37℃
である。癌細胞を普通細胞と区別する他の物理的
特性は癌細胞が普通細胞より低い温度で死ぬこと
である。普通細胞が死ぬであろうまた普通細胞機
能をなし得なくなるであろう温度は平均46.5℃で
ある。癌細胞はこれに反し低い温度45.5℃で死滅
する。癌細胞を死滅させるに必要な温度上昇程度
は少なくも約８℃と測定されるが、普通細胞は少
なくとも9.5℃の温度上昇に耐え得る。
したがつて定つた温度上昇を精密に調整して普
通細胞の死滅以前に癌細胞を選択的に絶滅出来る
ことは知られている。この知られた温度特性の差
違に基づいて体内の癌細胞を加熱して癌治療をす
る多数の細胞外方法が試みられている。この治療
法を異常高熱法という。癌細胞をこの高温にする
為、研究者は高熱誘起、高熱浴利用、透熱療法、
熱ろう応用および癌領域に種々の加熱装置挿入を
含む多数の方法を試みたのである。
この時点で癌治療の種々の方法はいずれも本当
に有効ではなく、いずれも癌細胞から治療して問
題を解決しようとする共通性をもつている。癌細
胞の外部膜は脂質と蛋白質より成り熱伝導性は小
さいので、細胞を死滅させる迄細胞内温度を上昇
しなければならない様な場合に細胞内に到達させ
ることは外部からの加熱では困難である。前の異
常高熱法の細胞外手段により癌細胞絶滅に適当な
細胞内温度とする程高く温度を上げたならば加熱
した近くの多くの普通の細胞は全く死滅するであ
ろう。
本発明は、第１の発明において、直径１ミクロ
ンを超えない誘導加熱性粒子を水溶液中に懸濁さ
せて成ることを特徴とする該誘導加熱性粒子を癌
細胞内に吸収させて電磁場にさらし該粒子を誘導
加熱して癌細胞の癌細胞内温度を癌細胞を死滅さ
せるに十分な温度に上昇させるための静脈注射用
癌治療用組成物を提供するものである。
更に本発明は第２の発明において、誘導加熱性
粒子と癌搜索剤、癌治療用化学治療剤もしくはこ
の両者との組合せであつて直径１ミクロンを超え
ない大きさの固体組成物粒子を水溶液中に懸濁さ
せて成ることを特徴とする該固体組成物粒子を癌
細胞内に吸収させて電磁場にさらし該固個体組成
物粒子中の該誘導加熱性粒子を誘導加熱して癌細
胞の癌細胞内温度を癌細胞を死滅させるに十分な
温度に上昇させる且つ該固体組成物粒子中の癌搜
索剤、癌治療用化学治療剤もしくはこの両者を放
出させるための静脈注射用癌治療用組成物を提供
するものである。
上記固体組成物粒子は癌搜索剤、癌治療用化学
治療剤もしくはこの両者を複数の誘導加熱性粒子
で被覆した粒子の形体にあるのが好ましく、そし
て該被覆の厚さは0.1ミクロン以下であるのが好
ましい。
本発明は癌細胞内でまた原形質内で精確な加熱
温度上昇が出来る。細胞の外部膜又は細胞壁とし
て存在する熱障壁は従来細胞内での熱生成を防い
でいたが今や細胞内で生成した熱を保持する役目
に利用される。細胞基礎温度および細胞死滅に要
する温度に基づいて細胞を死滅させる為上げねば
ならない細胞上昇温度は精密を要する。普通細胞
に対する上昇温度は9.5℃であるが、癌細胞の上
昇温度は９℃である。故に癌細胞又は普通細胞に
おける温度上昇は少なくも8.0℃でありまた普通
細胞上9.5℃を超えない温度が普通細胞に害がな
く癌細胞を選択的に絶滅するのである。
本発明により癌細胞の細胞内温度上昇と細胞内
破壊を充分達成出来る多数の手段が発見される。
本発明の簡単広範な形態において、本発明は強
磁性、反磁性又は常磁性物質の様な微小粒子を癌
細胞に入れた後普通細胞を含む一般細胞全部を高
周波交流電磁場に入れる。
本発明のこの原理はまた癌細胞が普通細胞より
も導入される最小粒子の様な粒子および異物質に
対してより大きな親和力をもつという既知事実に
基づくものである。癌細胞の食作用特性によりこ
の粒子は癌細胞内で普通細胞内と比べて著しく多
数に濃縮される。この粒子導入後組織の電子顕微
鏡写真をとつた処癌細胞内における粒子の選択的
濃縮が明らかに示されている。これは癌細胞の高
速代謝作用に基づきまた腫瘍が新導管化に発展す
る為と予想される。腫瘍中に形成された新毛細管
および血管は普通組織の毛細管および血管と比べ
た場合外来粒子に大きな透過性をもつている。
本発明により有用な粒子は生体組織と適合する
強磁性粒子の様なものが有用である。同様に有用
な反磁性および常磁性物質にはガリウム、インジ
ウム、テクネチウム、ストロンチウム、よう素が
あり生体組織と適合する反磁性および常磁性物質
ならよい。粒子の粒子大きさは約１ミクロンを超
えてはならない。好ましい粒子大きさは１ミクロ
ンより小さいものである。
上記微小粒子は適当する液体賦形剤を用いて患
者に静脈注射される。デキストラン、ぶどう糖、
（生理）食塩又は血液の様な生体がうけ入れる物
質の水溶液および単に水が使用出来る。液体賦形
剤は後で注射の為粒子を懸濁させておく必要があ
る。有用な生体のうけ入れる物質の濃度は水中約
50重量％迄のものである。普通約１乃至10％の溶
液が適当する。溶液中の粒子濃度は精密を要せず
普通、溶液１c.c.当り50乃至75mgの範囲である。
患者への静脈注射は一般に患者の体重キログラ
ム当り１乃至10mgの粒子を１回に注射する様な量
で行なう。しかしこの１回の薬量は体重キログラ
ム当り約20〜45mgの粒子に迄増大させることがで
きる。患者の体重が大きい程投与しうる薬量は大
きい。このような薬量は注射は24〜72時間内に２
〜３回くりかえすことができる。２−３回注射の
全薬量は重要でなく24−72時間内に注射出来る。
注射時間間隔は患者および目的により大きく変え
られる。
水溶媒質中に含まれる微小粒子は血流で運ば
れ、普通細胞中に入るよりもずつと多く、また実
際ある場合には可能な限り普通細胞を除外し癌細
胞によつて食われると発見されている。
癌組織の電子顕微鏡写真は癌細胞の磁性粒子選
択取得を証明している。
これは第５図〜第８図から明らかである。第５
図および第６図は癌細胞（乳腺の悪性腫瘍）をも
つラツトにFe3O4粒子のデキストラン水溶液中の
懸濁液（10mg／c.c.）の２c.c.を静脈注射して48時間
後にとつた該ラツトの組織の電子顕微鏡写真であ
る。Fe3O4粒子は癌細胞に選択的に取得され（矢
印参照）、周囲の正常な線維母細胞には取得され
ていない。第７図は上記ラツトについて同様に静
脈注射をして48時間後にとつた肝臓細胞（癌細胞
は認められず軟組織である）の電子顕微鏡写真で
ある。Fe3O4粒子は殆ど取得されておらず、
Kupffer細胞中にごく僅かまれに取得されること
があるにすぎない。第８図は同様の試験において
転移癌細胞によつて取得されFe3O4粒子（矢印参
照）を示す電子顕微鏡写真である。この場合にも
周囲の正常細胞にはFe3O4粒子は取得されていな
い。
本発明の細胞内特性は明らかである。癌細胞内
温度は普通細胞を損なわずに癌細胞を死滅させる
様8.0乃至9.5℃に上昇出来ることがが発見されて
いる。
本発明の次の段階は高周波交流電磁場を用いて
誘導加熱して細胞温度を正確に上昇することであ
る。ヒステリシスを用いて誘導加熱する原理は知
られた原理である。同様に生体細胞の温度監視法
は医科学に既知の現に使用されている方法であ
る。
このような方法は癌細胞と正常細胞とに及ぼす
熱の効果の相違についての研究に関連して多年に
わたつて行なわれており、たとえば次の報文に記
載されている。
(i) “Hyperthermia and Cancer”，Vol.及び
，Ned B.Hornback編、CRC Press発行
（1984）
(ii) Robert Love，et、al，“Cancer Res.”30
pp 1525−30（1970）
(iii) Eliot Levine，et al.“J.Cell Physiol.”76
pp 373−380（1976）
微小粒子の誘導加熱は高周波範囲内で操作する
電子発振子を用いて大きいが普通の螺旋コイル内
の強力高周波電場に粒子を入れ電場エネルギーを
ヒステリシス損失と渦電流の抵抗的消滅による熱
に転化して行なわれる。螺旋誘導コイルは患者が
とおるに充分な内径をもち患者の体長を包む様な
長さのものとする。一般に内径は少なくとも
0.6mを必要とするが内径0.9〜1.8m以上のものが
好ましい。実際的および経済的観点から必要であ
る以外最大径はわかつていない。1.8m以上の直
径の誘導コイルは患者により均一なフラツクス勾
配を与えるので全操作において好ましい効果をも
つ。
交流高周波電磁場の周波数は50キロヘルツから
10メガヘルツ迄の範囲で振動子−発生器の入力は
患者体重キログラム当り0.5乃至1.0キロワツトの
範囲である。体重キログラム当り入力0.75キロワ
ツトが特に便利とわかつている。この入力と周波
数範囲でコイルは400乃至800エルステツド、成可
く550乃至650エルステツドを発生する様選ぶ。
処理される細胞内にある微小粒子を誘導加熱す
るに必要な時間は実質的に交流電磁場をつくる周
波数と入力に依り、結局発生電磁場強度に依る。
一般に患者を５乃至12分間又は好ましくは８乃至
10分間交流電磁場に入れれば少なくとも8.0℃の
大体必要な温度上昇に適当なことがわかつてい
る。重要なことは癌細胞を約8.0℃上昇させるこ
とのみが必要であつて、必要な温度に達する限り
賦形剤中の粒子の型および濃度および電磁処理に
関する条件に関する条件は重要なものではない。
実施例 １
本発明の最も簡単な形の特定実施例として５％
ぶどう糖水溶液中に0.7ミクロン大きさの水酸化
第２鉄粒子を約50mg／c.c.の量で懸濁させた。体重
キログラム当り30mgの薬量を24時間間隔で２回静
脈注射した。次いで患者を直径0.9mの誘導コイ
ル内に全身入れて電磁治療を用意した。コイルを
交流発生機につなぎ３メガヘルツの高周波、600
エルステツドの磁場を発生した。最後の注射12時
間後に患者の電磁治療を行なつた。癌細胞内粒子
の誘導加熱を８乃至10分行ない、その間細胞内温
度は8.5℃上昇した。この温度で生体組織内の癌
細胞は絶滅したが普通細胞は通常の細胞機能を回
復する。
この結果は癌細胞と正常細胞とに及ぼす熱の効
果の相違についての研究を報告した前記(i)、(ii)お
よび(iii)の報文に照らして妥当である。
本発明の最も簡単な形態な詳細記述したが癌細
胞用磁性粒子の選択性は種々の方法によつて高め
ることが出来る。
放射性同位元素の様な癌細胞搜索剤又は腫瘍特
効抗体の添加は微小粒子を癌細胞に選択的に向け
るに有用である。放射性同位元素および腫瘍特効
抗体はいずれも癌細胞に親和力をもちそれらがあ
る腫瘍の治療に使用出来るとわかつたのはこの理
由である。また放射性同位元素は磁性粒子の代り
に用い癌細胞によつて選択的に取得される様静脈
注射出来る。これら放射性同位元素の多くは元来
常磁性又は反磁性であり、単独に使用しても或い
は放射能をもたない任意の他の粒子と化学的に又
は物理的に混合して使用しても、交流電磁場の磁
性粒子および（又は）放射性同位元素に及ぼす効
果は癌細胞の温度をその死滅温度に迄上昇させ
る。有用な放射性同位元素の代表的例としてはガ
リウム−67、インジウム−113m、テクネチウム
−99m、ふつ素、セレン−75がある。上のものは
単に例で多くの他の放射性同位元素も有用であ
る。放射性同位元素単独又は微小粒子に結合した
ものの大きさおよび濃度および注射法は全く前記
した処と同じである。
この放射性同位元素は抗体は過去に肺臓走査に
ついてよう素−131（放射性同位元素）がアルブミ
ンに結合した様に粒子に結合出来る。例えば抗体
は中間還元性グルコース単位又はメタサツカリン
酸の様なその誘導体を使用することによつて強磁
性、常磁性又は反磁性粒子に普通の方法（たとえ
ばI131をアルブミンに結合させる下記(iv)および(v)
の報文中に記載の結合方法）により結合し、且つ
高分子量デキストランが水酸化第２鉄に結合する
（下記の実施例３参照）のと同様に、結合する。
(vi) J.P.Hugues，et，al.“Lab.Investigation”12
（10），pp 1009−17（1963）
(v) “The Textbook of Surgery”Davisおよ
びChristopher編，W.B.Saunders Co.発行、
pp 259−270（1977）
癌の１患者から取つた癌細胞を他の患者に注射
することによつて抗体が出来ることは知られてい
る。癌細胞の注射は元の供給者からの外来腫瘍細
胞に対する防禦物として変つた宿主中に抗体を順
に生成する。次いでこの抗体は選択的に分離され
過去では選択された特殊腫瘍治療に使われたので
ある。抗体は本発明において選択的癌細胞搜索剤
として有用である。
この抗体は微小粒子と化学的又は物理的に結合
させた後治療する患者に再注射出来る。元の腫瘍
細胞に対する抗体の特異性によつて粒子に結合し
た抗体は選択的に粒子の癌細胞によつて吸収され
易くさえする。
放射性同位元素をもつ抗体は、抗体を生産させ
る動物に放射性同位元素標識アミノ酸（抗体構成
成分）を与えて飼育し、この動物内で合成され放
射性同位元素標識抗体を集めることによつてえら
れる。このような技術はたとえば下記の報文(iv)に
記載されている。
(iv) D.Pressman，et al.，“Cancer Research”
17 pp 845−850（1957）。
巨大分子は抗体分子に結合出来る。蛋白質はジ
アゴタイズ（diagotize）されたアトキシル（ｐ
−アミノベンゼン砒酸）によつて抗体分子に結合
できる。抗体は蛋白質にも結合するがハプテン又
は抗原にも結合する。これは結合過程で抗体の免
疫学的に特異な位置を保護する。
重要なことは粒子又は放射性同位元素の選択的
方向の全くの目的は交流電磁場の存在が細胞温度
を8.0乃至9.5℃の範囲に上昇する熱を細胞内に生
ずることである。故にもしすべての細胞が等濃度
の粒子にもつていても誘導加熱応用によりすべて
の細胞で望む範囲内の同じ温度上昇となり普通の
細胞は損なわれないが癌細胞は死滅する。癌細胞
の食作用特によつて普通細胞中に粒子濃度が高く
なる危険はないと思うが、磁性粒子すべてを有効
に使いまた最小薬量で可能とする為に有利なら放
射性同位元素又は抗体の様な癌細胞選択的搜索剤
を利用することが望ましい。この方法で磁性粒子
の高濃度が癌細胞内に発見されまた普通細胞内に
は粒子が排除されないにしても非常に小量とな
る。
本発明による放射性同位元素の使用実施例を次
に記述する。
実施例 ２
くえん酸ガリウム−ガリウム−67を殺菌した等
浸透圧（等張）の５％食塩溶液中に混合し濃度を
全組成物１c.c.当りガリウム−67を１ミリキユーリ
ーとした。注射量は体重１Kg当り0.02乃至0.1ミ
リキユーリーの間で変え得る。注射後12時間をお
いてガリウム自体が分離して癌細胞内に選択的に
集まつた。細胞内のガリウムの釣合いに関する詳
細は下記の報文に記載されている。
(vii) PDR−Radiopharmaceutical USA
(viii) Sephton，et al.，Int′l.Nuclear Medicine
and Biology ８ pp 323−31（1981）
この後実施例１に記載したと全く同様の交流電磁
場を与えた。細胞内温度上昇は8.0乃至9.5℃とな
り普通細胞を損なうことなく癌細胞の選択的死滅
となつた。
ガリウム−67を癌搜索剤として利用しようとす
る場合よう素−131をアルブミンと結合させる方
法（前記(iv)）または(v)の報文参照）により粒子に
結合させ得る。この結合ガリウム粒子は全く同じ
方法で患者に注射出来るしガリウムが癌細胞に粒
子を選択的に引渡すことがわかつた。この選択的
引渡しは前記(vii)または(viii)の報文に照らして妥当
で
ある。この後癌細胞を交流電磁場に入れた場合癌
細胞内温度は癌細胞を選択的に絶滅する限界上昇
8.0℃以上に上昇した。
化学治療剤、放射性同位元素又は腫瘍特効癌抗
体の様な腫瘍特効癌剤の知られた利用法は本発明
によつて利用出来る。例えば化学治療剤には５−
フロロウラシル、ハロゲン化アルキルアミンたと
えばメチルビス（２−クロロエチル）アミン、ア
クチノマシンＤ、メトトレクセイト、シトクソン
およびヴインクリスチンおよび同じ用途に知られ
た他の薬剤がある。大きさ１ミクロンより小さい
知られた化学治療剤を強磁性物質で被覆し全粒子
大きさ約１ミクロン以下とすることも本発明の１
形態である。要するに粒子が化学治療剤を包み化
学治療剤の周りに微小球を形成するのである。磁
性粒子膜の厚さは約0.1ミクロンでなければなら
ない。故に全粒子大きさが１ミクロンを超えずそ
れより小さい方がよいので化学治療剤粒子大きさ
は約0.1ミクロン又はそれ以下であるべきである。
実施例 ３
0.ミクロンの粒径をもつ水酸化第二鉄粒子を１
c.c.当たり約50mgの濃度で５％デキストローズ水溶
液に懸濁させ、この懸濁液を癌細胞をもつ
Spraugt−Dawleyのラツト群に尾部静脈から注
射した。この注射の約48時間後に試験ラツト群を
交流発電機に接続した誘導コイル内においた。約
450キロヘルツの周波数および600エールステツド
の磁界強度を４〜５分間適用した。この期間中に
細胞内温度は３〜４℃上昇した。電磁エネルギー
にさらした後の48時間目、72時間目および96時間
目に組織試料を除き、電子顕微鏡で癌細胞の変化
を調べた。
第１図は対照標準動物（上記の処理をしなかつ
たラツト）からとつた癌細胞組織の11000×（倍
率）での電子顕微鏡写真である。このラツトの癌
細胞は通常の核および原形質の外観を示してい
る。核はクロマチン（染色質）の良好な核分散に
よりはつきりしている［下段付近のほぼ中央部分
参照］。原形質はミトコンドリアの通常の外観を
示していて、もとのままである［上段付近の左端
部分参照］。僅かの包含物により細胞境界の鮮明
さを欠いている［ほぼ中段の中央よりやや左側の
部分参照］。全体として、第１図の写真は癌細胞
の通常の電子顕微鏡的外観を示しているといえ
る。
第２図は上述の電磁エネルギーにさらした後の
48時間目の組織試料の倍率11000×でとつた同様
の顕微鏡写真である。誘起された細胞生成物
（ICP）の生産の変化特性が顕著にでている。こ
れらの変化は核および原形質の両者レベルで起つ
ている。核の変化はクロマチン過多を伴うクロマ
チンの周辺局限化から成り［下段の３個の濃色ブ
ロツク参照］、原形質の変化は細胞膜の色素の増
大および含有物の数の増大を包含する［上記の濃
色ブロツクよりやや上の部分参照］。これらの細
胞学的変化は細胞の代謝活性の増加につれて確実
に生じる。
第３図は処理後72時間目の組織試料の倍率
11000×でとつた同様の電子顕微鏡写真である。
色素の強化と共にクロマチンの更なる周辺局限化
が注目される［下段左端から中段ほぼ中央を経て
下段右端に至る４個の濃色ブロツク参照］。原形
質の変化の進行も細胞含有物の数の増加ならびに
誘起された細胞生成物の生産がつづく際のミトコ
ンドリアの膨潤によつてわかる［下段左端から中
段ほぼ中央部にかけての白色区域参照］。
第４図は処理後96時間目の組織試料の倍率
11000×でとつた同様の電子顕微鏡写真である。
上述の変化がこれらの細胞中で更に続いている。
色素の強化と共にクロマチンの更なる周辺局限化
が進行し［図面の周囲に存在する多数個の濃色ブ
ロツク参照］、原形質の変化も進行している［中
段の中央付近および下段の中央付近参照］。
実施例 ４
実施例３で使用する様な強磁性粒子はまた細胞
の温度より高い普通細胞の死滅温度より低い融点
をもつワツクスの様な低融点物質を含んでもよ
い。この温度範囲は約37乃至46.6℃である。この
ワツクスは強磁性物質と混合して実施例３の様に
応用される。この別の実施態様において実施例１
の様な交流電磁場を応用すると強磁性物質の誘導
加熱によつて低融点固体がとけ癌細胞内に化学治
療剤が放出される。同様に他の腫瘍特効癌剤を利
用出来る。
上記のとおり放射性同位元素又は抗体の様な癌
搜索剤は化学的治療剤を含む微小球を特殊癌細胞
へより選択的に指向けるに利用出来る。知られて
いるとおり化学治療剤はしばしば普通細胞に悪い
副作用をもつが、本発明法は化学治療剤を細胞内
で選択的に放出する、癌細胞中の化学治療剤の量
に比べて普通細胞中の化学治療剤濃度は最小とな
るであろう。普通細胞への望ましくない副作用は
したがつて全然避けることは出来ないにしても極
く僅かとなるにちがいない。
更に本発明の広範な性質を特徴づける実施態様
は実施例３に記載の方法で包んでいる強磁性微小
球内に腫瘍特効癌抗体又は癌治療用放射性同位元
素の混合法である。被覆した抗体又は放射性同位
元素はこの後癌細胞膜内に入れられ実施例４のと
おり交流電磁場を応用して強磁性物質の微小球に
抗体又は放射性同位元素の細胞内放出を起させ
る。包まれた物質の放出は実施例３に記載のとお
り細胞内で小球を溶解化することによつても可能
である。
本発明の重良要な特徴の一つは癌細胞が患者の
体内何処にあつても絶滅出来ることである。腫瘍
から離れ血管系又はリンパ液系中に浮遊の細胞も
本発明法によつて絶滅されてあろう。 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a composition for treating cancer within living tissue. In particular, the present invention relates to a therapeutic composition for use in a cancer treatment method that kills cancer cells intracellularly without damaging normal cells. There are currently many methods of cancer treatment, such as radiation therapy, chemotherapy, immunotherapy and surgery. The common feature of all of these methods and currently known methods is that they are of the extracellular domain, i.e. they apply killing forces or media from outside the cell to the cancer cells in an attempt to attack and exterminate the cells. It is something. This extracellular method has been found to be less effective because the outer membrane of cancer cells consists of two protein layers with a lipid layer in between, and it is difficult to penetrate the hard membrane. Even though extracellular methods have great significance in overcoming the cell membrane's protection, the attack on cancer cells usually has to be powerful enough to cause considerable damage to the cells and cause serious adverse effects on the patient. . This adverse effect has been found to significantly limit the efficacy and efficacy of this treatment. Safe and effective cancer treatments have long been a research goal. Ultimately, a method for successfully eradicating cancer cells must be selective to cancer cells and must not cause irreversible damage to normal cells. Ultimately, cancer therapy requires selectively distinguishing cancer cells from normal cells and selectively weakening or killing cancer cells without affecting normal cells. It is known that there are physical differences between cancer cells and normal cells. One major physical difference lies in the temperature differential characteristics between cancer cells and normal cells. Cancer cells have a higher basal temperature than normal cells because of their high metabolic rate. In living cells, the normal temperature of cancer cells is
It is known that the temperature is 37.5℃, but that of normal cells is 37℃.
It is. Another physical property that distinguishes cancer cells from normal cells is that cancer cells die at lower temperatures than normal cells. The average temperature at which cells will die and become unable to perform normal cell functions is 46.5°C. Cancer cells, on the other hand, die at a lower temperature of 45.5°C. The degree of temperature increase required to kill cancer cells has been determined to be at least about 8°C, while normal cells can tolerate temperature increases of at least 9.5°C. Therefore, it is known that cancer cells can be selectively exterminated before normal cells die by precisely adjusting a fixed temperature increase. A number of extracellular methods have been attempted to treat cancer by heating cancer cells within the body based on this known difference in temperature characteristics. This treatment method is called abnormal hyperthermia method. To bring cancer cells to this high temperature, researchers have used hyperthermia induction, the use of high-temperature baths, thermodialysis,
A number of methods have been tried including thermal wax application and insertion of various heating devices into the cancerous area. At this point, none of the various cancer treatment methods are really effective, and they all have one thing in common: they try to solve the problem by treating cancer cells first. The outer membrane of a cancer cell is made up of lipids and proteins and has low thermal conductivity, so when it is necessary to raise the temperature inside the cell to kill the cell, it is difficult to reach the inside of the cell using external heating. be. If the extracellular means of the previous hyperthermia method were to raise the temperature high enough to create an intracellular temperature suitable for killing cancer cells, many normal cells in the vicinity of the heating would die altogether. In the first aspect of the present invention, the induction heating particles having a diameter of not more than 1 micron are suspended in an aqueous solution, and the induction heating particles are absorbed into cancer cells and exposed to an electromagnetic field. The present invention provides a cancer treatment composition for intravenous injection, which increases the intracellular temperature of cancer cells to a temperature sufficient to kill cancer cells by inductively heating the particles. Furthermore, in the second aspect of the present invention, solid composition particles having a diameter not exceeding 1 micron, which are induction heating particles and a cancer detection agent, a chemotherapeutic agent for cancer treatment, or a combination of both, are dissolved in an aqueous solution. The particles of the solid composition, characterized in that the solid composition particles are suspended in cancer cells, are absorbed into cancer cells and exposed to an electromagnetic field, and the induction heatable particles in the solid composition particles are induction-heated to transform the cancer cells into cancer cells. A cancer treatment composition for intravenous injection for raising the internal temperature to a temperature sufficient to kill cancer cells and releasing a cancer detection agent, a chemotherapeutic agent for cancer treatment, or both in the solid composition particles. This is what we provide. Preferably, the particles of the solid composition are in the form of particles coated with a plurality of inductively heatable particles containing a cancer detection agent, a chemotherapeutic agent for cancer treatment, or both, and the coating has a thickness of 0.1 micron or less. is preferable. The present invention allows for precise heating temperature increases within cancer cells and within plasma. Thermal barriers present as the outer membrane or cell wall of cells, which traditionally prevented heat generation within the cell, are now used to retain the heat generated within the cell. The temperature at which the cell should be raised to kill the cell requires precision based on the basal cell temperature and the temperature required for cell death. The temperature increase for normal cells is 9.5°C, but the temperature increase for cancer cells is 9°C. Therefore, the temperature increase in cancer cells or normal cells is at least 8.0°C, and the temperature on normal cells that does not exceed 9.5°C does not harm normal cells and selectively kills cancer cells. The present invention has discovered a number of means capable of sufficiently increasing the intracellular temperature and destroying the cancer cells. In a simple and broad form, the invention involves introducing microparticles, such as ferromagnetic, diamagnetic, or paramagnetic materials, into cancer cells and then subjecting all normal cells, including normal cells, to a high-frequency alternating electromagnetic field. This principle of the invention is also based on the known fact that cancer cells have a greater affinity for introduced particles and foreign substances, such as the smallest particles, than normal cells. Due to the phagocytic properties of cancer cells, these particles are concentrated in significantly larger numbers within cancer cells than within normal cells. Electron micrographs of the tissue after introduction of the particles clearly show selective concentration of the particles within the treated cancer cells. This is expected to be due to the rapid metabolic action of cancer cells and the development of neovascularization of the tumor. New capillaries and blood vessels formed in tumors have greater permeability to foreign particles when compared to capillaries and blood vessels of normal tissue. Particles useful according to the present invention include ferromagnetic particles that are compatible with biological tissues. Similarly useful diamagnetic and paramagnetic materials include gallium, indium, technetium, strontium, and iodine, as long as the diamagnetic and paramagnetic materials are compatible with living tissue. The particle size of the particles should not exceed about 1 micron. Preferred particle sizes are less than 1 micron. The microparticles are injected intravenously into a patient using a suitable liquid vehicle. dextran, glucose,
(Physiological) Aqueous solutions of substances accepted by the body, such as saline or blood, and simply water can be used. A liquid vehicle is required to keep the particles suspended for later injection. The concentration of useful substances accepted by living organisms is approximately
up to 50% by weight. Usually about 1 to 10% solutions are suitable. The particle concentration in the solution is not critical and usually ranges from 50 to 75 mg/c.c. of solution. Intravenous injections into patients are generally administered at a single injection of 1 to 10 mg of particles per kilogram of patient body weight. However, this single dose can be increased to about 20-45 mg of particles per kilogram of body weight. The greater the patient's weight, the greater the amount of drug that can be administered. These doses are administered by injection within 24 to 72 hours.
Can be repeated ~3 times. The total dose for 2-3 injections is not critical and can be injected within 24-72 hours.
Injection time intervals vary widely depending on the patient and purpose. It has been discovered that microparticles contained in aqueous media are transported in the bloodstream and are eaten by cancer cells in larger numbers than normally enter cells, and in some cases exclude normal cells as much as possible. ing. Electron micrographs of cancer tissues demonstrate the selective acquisition of magnetic particles in cancer cells. This is clear from FIGS. 5 to 8. Fifth
The figure and Figure 6 show the results 48 hours after intravenously injecting 2 c.c. of a suspension of Fe 3 O 4 particles in an aqueous dextran solution (10 mg/cc) to rats with cancer cells (malignant tumors of the mammary gland). This is an electron micrograph of the tissue of the rat. Fe3O4 particles are selectively acquired by cancer cells (see arrow), but not by surrounding normal fibroblast cells. FIG. 7 is an electron micrograph of liver cells (no cancer cells were observed, the tissue was soft tissue) taken 48 hours after the same intravenous injection from the above rat. Few Fe 3 O 4 particles were obtained,
It is only occasionally acquired in Kupffer cells. FIG. 8 is an electron micrograph showing Fe 3 O 4 particles (see arrow) acquired by metastatic cancer cells in a similar study. In this case as well, no Fe 3 O 4 particles were acquired in the surrounding normal cells. The intracellular properties of the invention are clear. It has been discovered that the temperature inside cancer cells can be raised to 8.0-9.5°C, killing cancer cells without damaging the normal cells. The next step of the invention is to use high frequency alternating electromagnetic fields to precisely raise cell temperature through induction heating. The principle of induction heating using hysteresis is a known principle. Similarly, temperature monitoring of living cells is a method known and currently used in medical science. Such methods have been used for many years in conjunction with studies of the differential effects of heat on cancer cells and normal cells, and are described, for example, in the following publications: (i) “Hyperthermia and Cancer”, Vol., edited by Ned B. Hornback, published by CRC Press (1984) (ii) Robert Love, et, al, “Cancer Res.” 30
pp 1525−30 (1970) (iii) Eliot Levine, et al. “J.Cell Physiol.” 76
pp 373-380 (1976) Induction heating of small particles uses an electronic oscillator operating in the high frequency range to place the particles in a strong high frequency electric field in a large but ordinary helical coil and transfer the electric field energy to hysteresis losses and eddy current resistance. This is done by converting it into heat due to its disappearance. The helical induction coil should have a sufficient inner diameter for the patient to pass through and be long enough to encompass the length of the patient's body. Generally the inner diameter is at least
0.6 m is required, but an inner diameter of 0.9 to 1.8 m or more is preferable. The maximum diameter is not known unless it is necessary from a practical and economic point of view. Induction coils with a diameter of 1.8 m or more have a positive effect on the overall operation as they provide a more uniform flux gradient to the patient. The frequency of the alternating current high frequency electromagnetic field is from 50 kilohertz
In the range up to 10 MHz, the transducer-generator input ranges from 0.5 to 1.0 kilowatts per kilogram of patient weight. An input of 0.75 kilowatts per kilogram of body weight has been found to be particularly useful. For this input and frequency range, the coil is chosen to produce 400 to 800 oersteds, preferably 550 to 650 oersteds. The time required to inductively heat the microparticles within the cells being treated depends essentially on the frequency and input of the alternating electromagnetic field, and ultimately on the strength of the generated electromagnetic field.
Generally the patient is allowed to sit for 5 to 12 minutes or preferably for 8 to 12 minutes.
It has been found that 10 minutes of exposure to an alternating electromagnetic field is sufficient to achieve the approximate required temperature increase of at least 8.0°C. Importantly, it is only necessary to raise the cancer cells to about 8.0° C., and the conditions regarding the type and concentration of particles in the excipient and the conditions for electromagnetic treatment are not critical as long as the required temperature is reached. Example 1 As a specific embodiment of the invention in its simplest form, 5%
Ferric hydroxide particles with a size of 0.7 microns were suspended in an aqueous glucose solution in an amount of about 50 mg/cc. The drug was injected intravenously twice at 24 hour intervals at a dose of 30 mg/kg body weight. The patient was then placed whole body inside an induction coil with a diameter of 0.9 m to prepare for electromagnetic treatment. Connect the coil to an alternating current generator and generate a high frequency of 3 MHz, 600 MHz.
It generated an ersted magnetic field. Patients underwent electromagnetic treatment 12 hours after the last injection. Induction heating of cancer intracellular particles was performed for 8 to 10 minutes, during which time the intracellular temperature rose by 8.5°C. At this temperature, cancer cells in living tissues are extinguished, but normal cells recover their normal cell functions. This result is appropriate in light of the above-mentioned papers (i), (ii), and (iii), which reported studies on the difference in the effects of heat on cancer cells and normal cells. Although the simplest form of the present invention has been described in detail, the selectivity of magnetic particles for cancer cells can be increased by various methods. Addition of cancer cell hunting agents such as radioactive isotopes or tumor-specific antibodies are useful to selectively target microparticles to cancer cells. This is why both radioisotopes and tumor-specific antibodies have been found to have an affinity for cancer cells and can be used to treat certain tumors. Radioactive isotopes can also be used in place of magnetic particles and can be injected intravenously to be selectively acquired by cancer cells. Many of these radioactive isotopes are paramagnetic or diamagnetic in nature and can be used alone or mixed chemically or physically with any other non-radioactive particles. The effect of alternating electromagnetic fields on magnetic particles and/or radioactive isotopes raises the temperature of cancer cells to their killing temperature. Typical examples of useful radioactive isotopes include gallium-67, indium-113m, technetium-99m, fluorine, and selenium-75. The above are merely examples; many other radioisotopes are also useful. The size and concentration of the radioactive isotope alone or bound to microparticles, and the injection method are exactly the same as described above. This radioisotope allows antibodies to bind to particles, much as iodine-131 (a radioisotope) bound to albumin for lung scans in the past. For example, antibodies can be attached to ferromagnetic, paramagnetic or diamagnetic particles by the use of intermediate reducing glucose units or derivatives thereof such as metasacchulic acid (see (iv) below and (v)
and in the same manner as high molecular weight dextran is bound to ferric hydroxide (see Example 3 below). (vi) JPHugues, et, al. “Lab.Investigation”12
(10), pp 1009-17 (1963) (v) “The Textbook of Surgery” edited by Davis and Christopher, published by WBSaunders Co.,
pp 259-270 (1977) It is known that antibodies can be produced by injecting cancer cells taken from one cancer patient into another patient. Injection of cancer cells in turn generates antibodies in the transformed host as a defense against foreign tumor cells from the original supplier. This antibody was then selectively isolated and used in the past to treat selected specific tumors. Antibodies are useful as selective cancer cell searching agents in the present invention. The antibody can be chemically or physically conjugated to the microparticle and then reinjected into the patient to be treated. Due to the specificity of the antibody for the original tumor cell, the antibody bound to the particles may even selectively render the particles more susceptible to uptake by the cancer cells. Antibodies containing radioisotopes can be obtained by feeding an animal that produces antibodies with radioisotope-labeled amino acids (antibody constituents) and raising them, and collecting the radioisotope-labeled antibodies synthesized within the animals. Such a technique is described, for example, in the following report (iv). (iv) D.Pressman, et al., “Cancer Research”
17 pp 845−850 (1957). Macromolecules can bind to antibody molecules. Proteins are diagotized atoxyl (p
-aminobenzene arsenate) can be attached to antibody molecules. Antibodies bind to proteins, but also to haptens or antigens. This protects the immunologically unique location of the antibody during the binding process. Importantly, the entire purpose of the selective orientation of the particles or radioactive isotopes is that the presence of the alternating electromagnetic field generates heat within the cell that raises the cell temperature to a range of 8.0 to 9.5°C. Therefore, even if all cells were exposed to the same concentration of particles, the application of induction heating would cause all cells to have the same temperature rise within the desired range, leaving normal cells unharmed but killing cancer cells. I don't think there is any risk of high particle concentrations in normal cells, especially for phagocytosis of cancer cells, but if it is advantageous to use all the magnetic particles effectively and use the lowest possible dose, it is possible to use radioactive isotopes or antibodies, etc. It is desirable to use cancer cell-selective search agents. With this method, high concentrations of magnetic particles are found within cancer cells, and very little, if any, particles are eliminated within normal cells. Examples of the use of radioisotopes according to the invention are described below. Example 2 Gallium Citrate - Gallium-67 was mixed into a sterile isotonic 5% saline solution at a concentration of 1 milliCurie of gallium-67 per c.c. of total composition. The injection volume can vary between 0.02 and 0.1 millicuries per kg of body weight. Twelve hours after injection, gallium itself separated and selectively gathered within cancer cells. Details regarding intracellular gallium balance are described in the following paper. (vii) PDR-Radiopharmaceutical USA (viii) Sephton, et al., Int′l. Nuclear Medicine
and Biology 8 pp 323-31 (1981) Thereafter, an alternating current electromagnetic field exactly as described in Example 1 was applied. The intracellular temperature rose to 8.0 to 9.5°C, resulting in selective killing of cancer cells without damaging normal cells. When gallium-67 is to be used as a cancer-detecting agent, it can be bound to particles by the method of binding iodine-131 to albumin (see the report in (iv) or (v) above). The bound gallium particles can be injected into patients in exactly the same way, and the gallium was found to selectively deliver the particles to cancer cells. This selective delivery is appropriate in light of the reports in (vii) or (viii) above. After this, when cancer cells are placed in an alternating current electromagnetic field, the temperature inside the cancer cells rises to the limit that selectively annihilates the cancer cells.
The temperature rose to 8.0℃ or higher. Known uses of tumor-specific cancer agents, such as chemotherapeutic agents, radioisotopes, or tumor-specific cancer antibodies, can be utilized in accordance with the present invention. For example, chemotherapeutic agents include 5-
Fluorouracil, halogenated alkyl amines such as methylbis(2-chloroethyl)amine, actinomysin D, methotrexate, cytoxon and vincristine and other drugs known for the same use. It is also a feature of the present invention to coat known chemotherapeutic agents that are less than 1 micron in size with a ferromagnetic material so that the total particle size is less than about 1 micron.
It is a form. In essence, the particles envelop the chemotherapeutic agent and form microspheres around the chemotherapeutic agent. The thickness of the magnetic particle film should be approximately 0.1 micron. Therefore, the chemotherapeutic agent particle size should be about 0.1 micron or less since the total particle size should not exceed 1 micron, but should be smaller. Example 3 Ferric hydroxide particles with a particle size of 0.1 micron were
The suspension containing cancer cells was suspended in a 5% dextrose aqueous solution at a concentration of approximately 50 mg per cc.
Spragt-Dawley rats were injected via the tail vein. Approximately 48 hours after this injection, test rats were placed in an induction coil connected to an alternator. about
A frequency of 450 kilohertz and a field strength of 600 oersted were applied for 4-5 minutes. During this period, the intracellular temperature increased by 3-4°C. Tissue samples were removed at 48, 72 and 96 hours after exposure to electromagnetic energy and examined for changes in cancer cells using an electron microscope. FIG. 1 is an electron micrograph at 11000× (magnification) of cancer cell tissue taken from a control animal (rat not treated as described above). The rat cancer cells show a normal nuclear and protoplasmic appearance. The nucleus is clear due to good nuclear dispersion of chromatin (see approximately the center area near the bottom). The protoplasm shows the normal appearance of mitochondria and is intact [see the leftmost part near the top row]. The cell boundaries lack clarity due to a few inclusions [see the part slightly to the left of the center in the middle row]. Overall, it can be said that the photograph in Figure 1 shows the normal electron microscopic appearance of cancer cells. Figure 2 shows the results after exposure to the electromagnetic energy described above.
A similar photomicrograph taken at 11000x magnification of a 48 hour tissue sample. The altered characteristics of induced cellular product (ICP) production are remarkable. These changes occur at both the nuclear and protoplasmic levels. Nuclear changes consist of a peripheral localization of chromatin with hyperchromatin [see the three dark blocks below], and protoplasmic changes include an increase in the pigmentation of the plasma membrane and an increase in the number of inclusions [see the dark blocks above]. See the part slightly above the block]. These cytological changes occur steadily as the metabolic activity of the cells increases. Figure 3 is the magnification of the tissue sample 72 hours after treatment.
A similar electron micrograph taken at 11000x.
It is noteworthy that the chromatin is further localized to the periphery along with the enhancement of the pigment [see the four dark-colored blocks from the left edge of the bottom row, through the center of the middle row, to the right end of the bottom row]. Progression of protoplasmic changes is also seen by an increase in the number of cellular inclusions and swelling of the mitochondria as the production of induced cellular products continues [see the white area from the left edge of the bottom row to approximately the center of the middle row]. Figure 4 is the magnification of the tissue sample 96 hours after treatment.
A similar electron micrograph taken at 11000x.
The changes described above continue in these cells.
As pigments become stronger, chromatin further localizes to the periphery [see the many dark blocks around the drawing], and changes in the protoplasm also progress [see near the center of the middle row and near the center of the bottom row] ]. Example 4 Ferromagnetic particles such as those used in Example 3 may also include a low melting point material such as wax, which has a melting point above the temperature of the cell but below the normal cell death temperature. This temperature range is approximately 37-46.6°C. This wax is mixed with a ferromagnetic material and applied as in Example 3. In this alternative embodiment Example 1
When an alternating current electromagnetic field is applied, the low melting point solid is melted by induction heating of the ferromagnetic material, and the chemotherapeutic agent is released into the cancer cells. Similarly, other tumor-specific cancer drugs can be used. As mentioned above, cancer hunting agents such as radioisotopes or antibodies can be used to more selectively target microspheres containing chemical therapeutic agents to specific cancer cells. As is known, chemotherapeutic agents often have adverse side effects on normal cells, but the method of the present invention selectively releases chemotherapeutic agents within cells, reducing the amount of chemotherapeutic agents in normal cells compared to the amount of chemotherapeutic agents in cancer cells. The concentration of chemotherapeutic agent therein will be minimal. Undesirable side effects on normal cells should therefore be minimal, if not entirely avoidable. An embodiment that further characterizes the broad nature of the invention is the mixing of tumor-specific cancer antibodies or cancer therapeutic radioisotopes within ferromagnetic microspheres encapsulated in the manner described in Example 3. The coated antibody or radioisotope is then introduced into the cancer cell membrane and an alternating electromagnetic field is applied as in Example 4 to cause the ferromagnetic microspheres to release the antibody or radioisotope intracellularly. Release of the encapsulated material is also possible by lysing the globules intracellularly as described in Example 3. One of the important features of the present invention is that cancer cells can be killed anywhere in the patient's body. Cells floating away from the tumor in the vasculature or lymphatic system may also be killed by the method of the present invention.
第１図〜第４図は実施例３の実験結果を示す
11000×（倍率）での試験動物（ラツト）の癌細胞
組織の電子顕微鏡写真である。第１図は本発明に
よる処理をしなかつたものの電子顕微鏡写真であ
る。第２図〜第４図は本発明に従い実施例３で述
べた処理を行つたものの電子顕微鏡写真であり、
第２図は処理後48時間目の、第３図は処理後72時
間目の、そして第４図は処理後96時間目の癌細胞
組織の変化をそれぞれ示す。第５図〜第８図は磁
性粒子の懸濁液を試験動物（ラツト）に静脈注射
してから48時間後にとつた該試験動物の細胞組織
の電子顕微鏡写真であり、癌細胞の磁性粒子選択
取得を示すものである。第５図および第６図は磁
性粒子が癌細胞（乳腺の悪性腫瘍）に選択的に取
得され（矢印参照）周囲の正常な細胞には取得さ
れないことを示し、第７図は肝臓細胞（正常）に
も磁性粒子は殆ど取得されないことを示し、そし
て第８図は磁性粒子が転移癌細胞にも選択的に取
得され（矢印参照）この場合にも周囲の正常細胞
には取得されないことを示している。
Figures 1 to 4 show the experimental results of Example 3.
It is an electron micrograph of cancer cell tissue of a test animal (rat) at 11000× (magnification). FIG. 1 is an electron micrograph of a sample not treated according to the present invention. FIGS. 2 to 4 are electron micrographs of products subjected to the treatment described in Example 3 according to the present invention,
Figure 2 shows changes in cancer cell tissue 48 hours after treatment, Figure 3 72 hours after treatment, and Figure 4 96 hours after treatment. Figures 5 to 8 are electron micrographs of cell tissues of test animals (rats) taken 48 hours after intravenously injecting a suspension of magnetic particles into the test animals. This indicates acquisition. Figures 5 and 6 show that magnetic particles are selectively acquired by cancer cells (mammary gland malignant tumors) (see arrows) and not by surrounding normal cells, and Figure 7 shows that magnetic particles are selectively acquired by cancer cells (mammary gland malignant tumors) and not by surrounding normal cells. ) also shows that almost no magnetic particles are acquired, and Figure 8 shows that magnetic particles are selectively acquired even in metastatic cancer cells (see arrow), and in this case also, they are not acquired in surrounding normal cells. ing.
Claims (1)
水溶液中に懸濁させて成ることを特徴とする該誘
導加熱性粒子を癌細胞内に吸収させて電磁場にさ
らし該粒子を誘導加熱して癌細胞の癌細胞内温度
を癌細胞を死滅させるに十分な温度に上昇させる
ための静脈注射用癌治療用組成物。 ２ 水溶液がぶどう糖、デキストラン、食塩又は
血液の１乃至10％水溶液である特許請求の範囲第
１項に記載の組成物。 ３ 粒子が強磁性、常磁性又は反磁性体である特
許請求の範囲第１項又は第２項に記載の組成物。 ４ 粒子が水酸化第２鉄又は酸化鉄である特許請
求の範囲第１項又は第２項に記載の組成物。 ５ 溶液中の粒子が溶液１c.c.当たり50乃至75mg含
まれる特許請求の範囲第１項から第４項迄のいず
れか１項に記載の組成物。 ６ 誘導加熱性粒子と癌搜索剤、癌治療用化学治
療剤もしくはこの両者との組合せであつて直径１
ミクロンを超えない大きさの固体組成物粒子を水
溶液中に懸濁させて成ることを特徴とする該固体
組成物粒子を癌細胞内に吸収させて電磁場にさら
し該固体組成物粒子中の該誘導加熱性粒子を誘導
加熱して癌細胞の癌細胞内温度を癌細胞を死滅さ
せるに十分な温度に上昇させる且つ該固体組成物
粒子中の癌搜索剤、癌治療用化学治療剤もしくは
この両者を放出させるための静脈注射用癌治療用
組成物。 ７ 水溶液がぶどう糖、デキストラン、食塩又は
血液の１乃至10％水溶液である特許請求の範囲第
６項に記載の組成物。 ８ 誘導加熱性粒子が強磁性、常磁性又は反磁性
体である特許請求の範囲第６項又は第７項に記載
の組成物。 ９ 誘導加熱性粒子が水酸化第２鉄又は酸化鉄で
ある特許請求の範囲第６項又は第７項に記載の組
成物。 １０ 癌搜索剤が放射性同位元素又は腫瘍特異性
癌抗体である特許請求の範囲第６項に記載の組成
物。 １１ 放射性同位元素がガリウム−67、インジウ
ム−113m、テクネチウム−99m、ふつ素又はセ
レン−75である特許請求の範囲第１０項に記載の
組成物。 １２ 固体組成物粒子が癌治療用化学治療剤を複
数の誘導加熱性粒子で被覆した粒子の形である特
許請求の範囲第６項に記載の組成物。 １３ 被覆の厚さが0.1ミクロン以下である特許
請求の範囲第１２項に記載の組成物。 １４ 癌治療用化学治療剤を複数の誘導加熱性粒
子で被覆した粒子が１ミクロンを超えない直径を
もつ特許請求の範囲第１３項に記載の組成物。 １５ 溶液中の粒子が溶液１c.c.当たり50乃至75mg
含まれる特許請求の範囲第６項から第１３項迄の
いずれか１項に記載の組成物。[Scope of Claims] 1. Induction heating particles having a diameter not exceeding 1 micron are suspended in an aqueous solution, and the induction heating particles are absorbed into cancer cells and exposed to an electromagnetic field. A cancer treatment composition for intravenous injection for increasing the intracellular temperature of cancer cells to a temperature sufficient to kill cancer cells by induction heating. 2. The composition according to claim 1, wherein the aqueous solution is a 1 to 10% aqueous solution of glucose, dextran, salt, or blood. 3. The composition according to claim 1 or 2, wherein the particles are ferromagnetic, paramagnetic or diamagnetic. 4. The composition according to claim 1 or 2, wherein the particles are ferric hydroxide or iron oxide. 5. The composition according to any one of claims 1 to 4, wherein the particles in solution are contained in an amount of 50 to 75 mg per c.c. of solution. 6 A combination of induction heating particles and a cancer detection agent, a chemotherapeutic agent for cancer treatment, or both, with a diameter of 1
The solid composition particles having a size not exceeding microns are suspended in an aqueous solution, and the solid composition particles are absorbed into cancer cells and exposed to an electromagnetic field to induce the induction in the solid composition particles. The heating particles are heated by induction to raise the temperature inside the cancer cells to a temperature sufficient to kill the cancer cells, and the cancer detection agent, the chemotherapeutic agent for cancer treatment, or both in the solid composition particles are An intravenous cancer treatment composition for release. 7. The composition according to claim 6, wherein the aqueous solution is a 1 to 10% aqueous solution of glucose, dextran, salt, or blood. 8. The composition according to claim 6 or 7, wherein the induction heating particles are ferromagnetic, paramagnetic or diamagnetic. 9. The composition according to claim 6 or 7, wherein the induction heating particles are ferric hydroxide or iron oxide. 10. The composition according to claim 6, wherein the cancer detection agent is a radioisotope or a tumor-specific cancer antibody. 11. The composition according to claim 10, wherein the radioactive isotope is gallium-67, indium-113m, technetium-99m, fluorine or selenium-75. 12. The composition of claim 6, wherein the solid composition particles are in the form of particles in which a chemotherapeutic agent for cancer treatment is coated with a plurality of inductively heatable particles. 13. The composition of claim 12, wherein the coating thickness is 0.1 micron or less. 14. The composition of claim 13, wherein the particles coated with a plurality of inductively heatable particles coated with a chemotherapeutic agent for cancer treatment have a diameter not exceeding 1 micron. 15 Particles in solution are 50 to 75 mg/c.c. of solution
A composition according to any one of the included claims 6 through 13.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8213978A JPS5511509A (en) | 1978-07-07 | 1978-07-07 | Cancer therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8213978A JPS5511509A (en) | 1978-07-07 | 1978-07-07 | Cancer therapy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5511509A JPS5511509A (en) | 1980-01-26 |
| JPS635379B2 true JPS635379B2 (en) | 1988-02-03 |
Family
ID=13766081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8213978A Granted JPS5511509A (en) | 1978-07-07 | 1978-07-07 | Cancer therapy |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5511509A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990001939A1 (en) * | 1988-08-19 | 1990-03-08 | Meito Sangyo Kabushiki Kaisha | Agent for thermotherapy |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55160720A (en) * | 1979-05-29 | 1980-12-13 | Mochida Pharmaceut Co Ltd | Remedial composition for cancer and its remedial device |
| JPS61128983A (en) * | 1984-11-27 | 1986-06-17 | 大山 國賀 | Fixing of fine powder in living body for definite period andheating of the same to arbitrary temperature |
| JPS61265153A (en) * | 1985-05-21 | 1986-11-22 | 高木 征一 | Induction heater for warming treatment |
| JPS6412545U (en) * | 1987-07-13 | 1989-01-23 | ||
| CN1744906B (en) | 2003-01-31 | 2010-08-18 | 株式会社大塚制药工厂 | Auxiliary agent to be used in cancer therapy by dielectric heating and cancer therapy method |
| US20060251584A1 (en) * | 2003-06-11 | 2006-11-09 | Nara Machinery Co., Ltd. | Drug nano-particle, method and apparatus for preparing pharmaceutical preparation using the particle |
| US7507842B2 (en) | 2005-08-12 | 2009-03-24 | Radiorx, Inc. | Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof |
| US20140308260A1 (en) | 2011-10-07 | 2014-10-16 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
| US10342778B1 (en) | 2015-10-20 | 2019-07-09 | Epicentrx, Inc. | Treatment of brain metastases using organonitro compound combination therapy |
| US9987270B1 (en) | 2015-10-29 | 2018-06-05 | Epicentrix, Inc. | Treatment of gliomas using organonitro compound combination therapy |
| ES2880482T3 (en) * | 2016-01-11 | 2021-11-24 | Epicentrx Inc | Compositions and methods for intravenous administration of 2-bromo-1- (3,3-dinitroazetidin-1-yl) ethanone |
| EA201990949A1 (en) | 2016-10-14 | 2019-10-31 | SULPHOXIALKYL ORGANIC NITRO COMPOUNDS AND RELATED COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR USE IN MEDICINE | |
| SG11201914046WA (en) | 2017-07-07 | 2020-01-30 | Epicentrx Inc | Compositions for parenteral administration of therapeutic agents |
| WO2019164593A2 (en) | 2018-01-08 | 2019-08-29 | Epicentrx, Inc. | Methods and compositions utilizing rrx-001 combination therapy for radioprotection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5649889A (en) * | 1979-10-01 | 1981-05-06 | Hiroshi Tanigaki | Cooler |
-
1978
- 1978-07-07 JP JP8213978A patent/JPS5511509A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5649889A (en) * | 1979-10-01 | 1981-05-06 | Hiroshi Tanigaki | Cooler |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990001939A1 (en) * | 1988-08-19 | 1990-03-08 | Meito Sangyo Kabushiki Kaisha | Agent for thermotherapy |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5511509A (en) | 1980-01-26 |
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