Perfluorochemicalsの癌化学療法への応用—C6ラット脳腫瘍モデルに対する効果

EFFECT OF PERFLUOROCHEMICALS ON BCNU CHEMOTHERAPY IN A RAT BRAIN-TUMOR MODEL

　抄録　悪性脳腫瘍における低酸素性細胞（hypoxic cell）の存在は，化学療法・放射線療法を行ううえで一つの大きな問題点と考えられている。一方perfluorochemicalsは，高酸素運搬能と微細な粒子という特徴を持ち，さらに脳微小循環改善作用も有している。この点に注目し，perfluorochemicalsの投与により，hypoxiccellをoxygenationし，腫瘍細胞の抗癌剤感受性を高め，同時に腫瘍内血流改善により抗癌剤の腫瘍内濃度を高める目的で，ラット脳腫瘍モデルを用いて治療実験を行った。脳腫瘍モデルは，ウィスターラット脳内にC₆ラットグリオーマ細胞を移植して作成した。脳内移植10日後に，perfluorochemicals （Fluosol−43）20ml／kgを静注し，高濃度酸素条件下でPaO₂を300mmHg以上に保ち1-3—bis （2—chloroethyl）−1—nitro—sourea （BCNU）をLD₁₀量腹腔内投与した。このFluosol−43とBCNU併用投与群と，無処置群，Fluosol—43投与群およびBCNU投与群の延命効果を比較検討した。Fluosol−43をBCNUに併用した群は，BCNU単独投与群に比べて，有意な延命効果を認めた（P＜0.005）。このperfiuorochemicalsの効果に関しては，hypoxic cellのoxygenationと同時に，腫瘍内hypovascular areaでの微小循環改善によって，薬剤の腫瘍内濃度が高められたという機序を考えた。

Perfluorochemicals (Fluosol-43) is characterized with its small size and high propensity for carrying oxygen and carbon dioxide, and also have the func-tion to improve the cerebral microcirculation. These characteristic features of Flusos1-43 may have a beneficial effect on brain-tumor chemothera-py in terms of the oxygenation of hypoxic cells, and/or the improvement of the pharmacokinetics of anticancer drugs.

This study was undertaken to identify the com-bined effect of perfluorochemicals (Fluosol-43, 20 m//kg) and chemotherapeutic agent (BCNU, LD₁₀ dose; 13.3 mg/kg) in a rat brain-tumor model.

Brain-tumor model was made by the intracere-bral implantation of C₆ rat glioma cells (1x10⁵ cells/10μl). At 10 days after implantation. control animals had a macrotumor weighing about 100 mg with large part of central necrosis. The tumor-bearing rats for 10 days after implantation were randomly divided into 4 groups; a control group, a Fluosol-43 treatment group, a BOND- treatment group, and a Fluosol-43 plus BCNU treatment group. Control animals had mean survival time of 19. 94±2. 41 (S. D.) days, and mean survival time of Fluosol-43 treatment group was 19. 47±1. 36 days. BCNU treatment alone prolonged the mean survival time to 28. 36±7. 94 days (p <0.001). Fluosol-43 plus BCNU treatment group showed 36.00±10. 15 days, which was significantly greater than that of BCNU treatment alone group (p< 0.005). The long survivals lived over 50 days after implantation were 7 out of 27 rats in Fluosol-43 plus BCNU treatment group, in contrast to one out of 25 rats in BCNU treatment alone group.

Perfluorochemicals (Fluosol-43) may have the synergistic effect on BCNU chemotherapy for brain tumors.

It was speculated for the above results that fol-lowing the oxygenation of hypoxic cells by Fluosol-43, hypoxic cells might be sensitized to BCNU, which might be much delivered into hypoxic area. And further studies should be done for the evalu-ation of the mechanism of perfluorochemicals on brain tumor experimentally before clinical applica-tion.