Interferon inducer （poly ICLC）の悪性脳腫瘍治療効果—基礎と臨床

EEFECT OF INTERFERON INDUCER (POLY ICLC) IN THE TREATMENT OF MALIGNANT BRAIN TUMOR

　抄録　合成二重鎖RNA,Poly ICはゲッ歯類においては優秀なinterferon inducerとして知られるが，interferon誘発能の割に発熱等の副作用が強く，臨床的に有効な結果をみるには至つていない。そこでpolyICをpoly L-Lysineで安定化したpoly ICLCを合成し，ラットにおけるinterferon誘発能，抗腫瘍効果，毒性について観察すると共に，臨床的にphase I,II studyを行つた。poly ICLCをラットに静注すると，同量のpoly ICに比べ高レベルの血中interferon価が長時間維持され，又poly ICLC 1mg／kg静注により，脳腫瘍ラットに対する有意な延命効果が認められたが，poly ICでは効果を認めなかった。臨床的には，poly lCLC0.05〜0.2mg／kgを9例の悪性脳腫瘍患者に点滴静注した。全例において100単位／ml以上の血中interferonピーク値が認められ，24時間にわたり維持された。今回のシリーズでは，poly ICLCは重症患者に投与される機会が多く，臨床効果の判定は早計であるが，1週間隔で10回以上与した2症例を含む3症例では神経症状の改善がみられ，1例ではCT scan上腫瘍の縮小をみとめた。副作用としては発熱が全例にみられたが，平均体温上昇は1.9℃にとどまり，poly ICより軽度であつた。又少数例で血圧低下，白血球減少，肝機能障害がみられたが，いずれも一過性であつた。

Interferferon inducing activity, antitumor activity and toxicity of poly ICLC (poly IC stabilized with poly L-Lysine and carboxymethyl cellulose) in rodents were studied. SD strain rats were injected intravenously with poly IC or poly ICLC. Inter-feron in rat plasma was assayed by a plaque reduction method using stomatitis virus. The peak level of plasma interferon of the poly ICLC injec-tion rat was as high as that of poly IC injectionrat, and in the former, high level of plasma in-terferon persisted for 4-12 hours. Next, brain tumor-bearing rats were treated intravenously with poly ICLC and observed for death daily. Weekly treatment with 1 mg/kg of poly ICLC increased the mean survival time although no antitumor effect was observed with poly IC. The LD 50 value of poly IC was 33.5 mg/kg, and that of poly ICLC was 18.6 mg/kg and as to poly ICLC administration, no remarkable side effect was recognized below the dose of 1.5 mg/kg.

In clinical trials, poly ICLC was given intrave-nously at the dose of 0. 05-0. 2 mg/kg to 9 patients with malignant brain tumor. (6 patients were glio-blastoma, 1 was astrocytoma, and 2 were epen-dymoma.) In 2 patients, poly ICLC was admini-stered once, in 2 patients twice, in 2 patients 3 times, and in 3 patients more than 5 times. The interval of each administration was 7 days. Poly ICLC induced high level of serum interferon (more than 100 reference unit/m/) in all patients and over 100 unit/m/ of interferon was maintained for 24 hours. The highest interferon titer induced was 875 unit/m/. The most frequently encountered toxic reaction was fever, which occurred in all cases. The mean peak temperature elevation was 1.9℃, which usually occurred 4-8 hours after drug administration. Modest hypotention was detected in one case. Leucopenia was detected in 3 cases. These abnormalities were all modest, and improved in a few days. As to the effect of poly ICLC, neurological improvement was recognized in 3 cases, and in one of them, remission on CT scan was also recognized.