3H-Methotrexateのマウス悪性Glioma内とりこみについて—とくに静脈内および髄腔内投与法の比較検討

CHEMOTHERAPY OF BRAIN TUMOR: THE UPTAKE OF 3H-METHOTREXATE BY MOUSE GLIOMA

Ｉ．緒言

　脳腫瘍の化学療法にあたり，有効な制癌剤の開発とともに重要な問題は，いかにして制癌剤を十分脳腫瘍にとりこませるかということである。この目的のため制癌剤の選択および投与法が積極的に研究されてきた。しかしいまだ制癌剤の脳腫瘍内とりこみに関する研究は少なく，とくに最近普及してきた制癌剤の髄腔内投与後の脳腫瘍内とりこみについての報告は極めて少ない。われわれの教室では早くから制癌剤の髄腔内投与に注目し系統的に研究を進めてきたが^1）〜5），今回は実験対象として，従来の脳内移植腫瘍と異なり，より人脳腫瘍に近い薬剤誘発原発性gliomaを用い，静脈内および髄腔内に投与した制癌剤のglioma内とりこみについて基礎的研究を行なつたので報告する。

As the maximum effects of chemotherapeutic agents would be considered to occur when they concentrate preferencially in the tumor, it was felt that a knowledge of the uptake and distribution of the drugs in malignant gliomas might improve their clinical usefulness. This study was initiated to determine the uptake and distribution of Metho-trexate in mouse glioma after intravenous or intrathecal administration, and to estimate the effectiveness of the drug by various routes of ad- ministration for treatment on the patients with malignant glioma.

Brain tumors were induced in male mice of strain ddN of approximately 5 weeks old and weighed 15 g by intracerebral implantation of 20-methyl-cholanthrene pellet of approximately 1 mg in weight. Tritiated Methotrexate (³H-MTX) (0.55 mCi/mg) was injected intravenously (1.80 ,ug/g of body weight) or intrathecally (0.18 ,ug/g of bodyweight) into mice bearing induced brain tumor. The mice were bled to death at various hours after the injection and distribution of 3H-MTX was determined by counting of radioactivities in tissue and by radioautography (tissue freeze-dried, embeded in Epon).

Gliomas were induced in 31 mice at 9.2 months on average after the implantation of 20-methyl-cholanthrene pellet, and used in this study. They were very similar histologically to the human glioblastoma. Sixteen mice with induced fibro-sarcoma of meninges were also used.

The amount of ³H-MTX taken up by the gliomas was considerably high with a significant tumor brain concentration ratio ranging from 2 to 13 after either route of administration. The uptake of ³H-MTX by gliomas at 24 hours after intrathecal administration exceeded that obtained after intra-venous injection, though the dose of the drug administered was one tenth of that of intravenous injection, and the concentration ratio between glioma and brain ranged from 5 to 11. The uptake of ³H-MTX by sarcoma of meninges was less than that of glioma and the tumor to brain concentration ratio was from 1.2 to 5.2, and no difference was noted in the uptake between intravenous and in-trathecal administration.

Radioautographic distribution study of ³H-MTX revealed that ³H-MTX had largely penetrated into the neoplastic cells of malignant gliomas at 24 hours after intravenous and intrathecal administra-tion.