ACNU髄腔内投与後の頭蓋内分布—Macroscopicalautoradiographyによる検討

DISTRIBUTION OF ACNU IN THE RAT BRAIN AFTER INTRACISTERNAL INJECTION:MACRO-SCOPICAL AUTORADIOGRAPHIC STUDY

　抄録　悪性leptomeningeal tumorに対するACNU髄腔内投与の妥当性を知る目的で，正常ラットの大槽髄腔内に経皮的に投与したACNUの頭蓋内分布を，¹⁴C-ethylene-ACNUをtracerとするmacro-scopical autoradiography法により観察した。その結果，¹⁴C-ACNUは投与後5分で脳底部，迂回槽，海馬溝などのクモ膜下腔とそれに面する浅い脳表層に速やかに分布した。投与後30分では既にclearanceのため全体の分布量は低下し，5分後よりさらに脳深部へ浸透する所見はなく，投与後3時間では脳表層に痕跡程度残存するのみであった。したがって，全身投与などの他の投与法に比較すると，ACNU髄腔内投与によりleptomeningeal tumorに対しては短時間ではあるが高濃度の薬剤分布が得られ，しかも正常脳組織に対する毒性は少ないと考えられる。この結果より，本投与法は悪性leptomeningeal tumorに対する新しい治療法となりうることが示唆された。

In the previous reports, we demonstrated that intracisternal ACNU is effective in prolonging the survival time of rats with meningeal carcino-matosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, and systemic and local toxicity can be avoided by adjusting the drug dose. In this experiment, we studied distri-bution of ¹⁴C-ACNU in the rat brain after intra-cisternal administration using a macroscopical autoradiographic method. One μCi of ethylene-¹⁴C-ACNU was percutaneously injected into the cisterna magna of normal female Wistar rats weighing approximately 150 g. The animals were acri ficed 5 and 30 minutes, and 3 hours after injection (3 animals in each group). The brain was quickly removed and frozon in Freon. ¹⁴C-ACNU autoradiograms were made in coronal sections of the brain, which were cut in 20μthick and exposed to the film for 7 days. In 5 minutes after administration, high radioactivity was distributed in the subarachnoid space of the basal and ambient cisterns and hypocampal fis-sures, and subpial brain tissue up to 1 or 2 mm in depth. High radioactivity was also present in the ventricles and subependymal layer. In 30 minutes after administration, total radioactivity has already reduced in amount, however, local distribution has not changed so much as compared to that of 5 minutes after injection. No radioactivity was observed in the deeper part of the brain. In 3 hours after administration, only a small amount of radioactivity remained in the subarachnoid space and subpial region. These results indicate that intracisternally injected ACNU is rapidly cleared from the cerebrospinal fluid space and from the subpial brain tissue into the systemic circulation, and cannot penetrate into the deeper part of the brain by diffusional transport. Distri-bution profiles of ¹⁴C-ACNU in the brain observed in this study suggests that intrathecal ACNU could be a useful treatment for human malignant leptomeningeal tumors.