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Neurological Surgery No Shinkei Geka Volume 26, Issue 10 （October 1998）

Neurological Surgery 脳神経外科 26巻10号（1998年10月発行）

Japanese English

研究

5-fluoro-2'deoxyuridine（FdUrd）の髄腔内治療への応用に関する研究—髄腔内治療の可能性に関してin vivoでの検討 In vivo Study on Intrathecal Use of 5-fluoro-2'-deoxyuridine (FdUrd) in Meningeal Dissemination of Malignant Tumor 中川秀光 ¹ , 山田正信 ¹ , 福島正和 ² , 清水恵司 ³ , 池中一裕 ⁴ Hidemitsu NAKAGAWA ¹ , Masanobu YAMADA ¹ , Masakazu FUKUSHIMA ² , Keiji SHIMIZU ³ , Kazuhiro IKENAKA ⁴ ¹大阪府立成人病センター脳神経外科 ²大鵬薬品株式会社，創薬センター，第二癌研究所 ³大阪大学脳神経外科 ⁴国立岡崎共同研究機構，生理学研究所 ¹Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases ²Cancer Research Laboratory, Taiho Pharmacological Co. ³Department of Neurosurgery, Osaka University Medical School ⁴Laboratory of Neural Information, National Institute for Physiological Sciences, Okazaki National Research Institutes キーワード： brain tumor , fluorodeoxyuridine , thymidine phosphorylase , thymidine kinase , intrathecal chemotherapy Keyword: brain tumor , fluorodeoxyuridine , thymidine phosphorylase , thymidine kinase , intrathecal chemotherapy pp.873-879

発行日 1998年10月10日 Published Date 1998/10/10

DOI https://doi.org/10.11477/mf.1436901621

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Abstract 文献概要
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I．はじめに

　5-fluoro-2'-deoxyuridine（FdUrd）は，5-fluo-rouracil（5-FU）の活性代謝物であり，それ自体極めて強い抗腫瘍活性を有し，米国では大腸癌の肝転移に対する治療薬として肝動注療法としてのみ使用されている公知の化合物である^7,8,15）．かつて，FdUrdは転移性脳腫瘍に対する臨床応用はあるものの，いずれも静脈内投与での極少数例による成績で治療効果も確定するに至っていない^5）．このFdUrdは生体内でthymidine kinase（TK）によって代謝を受けintracellular monophosphatederivativeである5-fluoro-2'-deoxyuridine-5'-monophosphate（FdUMP）に変換されるとともにメチレンテトラヒドロ葉酸とともにDNA合成のkey enzymeであるthymidylate synthaseとter-nary complexを形成することにより，これを阻害してcytotoxicityを発現する^2-4,6,14）．一方FdUrdはthymidine phosphorylase（TPase）により5-FUへ異化されることからFdUrdの抗腫瘍効果の減弱に働き，また一部はfluoro-β-alanineに変換され神経毒性を引き起こす^12,13,17）．

FdUrd was evaluated in vivo as a potential agent for intrathecal chemotherapy of meningeal carcinoma-tosis. Neurotoxicity was examined pathologically in normal mice after 4 consecutive intrathecal injectionsof FdUrd. Using mice models of meningeal carcinomatosis, antitumor activities were studied by evaluatingsurvival time. Pathological examination showed none of the following abnormal findings : demyelination,degeneration and destruction of ependymal linings. FdUrd also had an effect on meningeal carcinomatosisof mice (203 glioma and MM46 transplantable ascitic mammary cancer). In causing FdUrd to exhibit itsefficacy, it is necessary to take into consideration the balance between the activity of two key enzymes,thymidine phosphorylase (TPase) (anabolic enzyme) and thymidine kinase (TK) (metabolic enzyme), intumor tissues as compared with their activity in normal tissues. TPase activity which results inconversionto 5-FU was much lower in malignant glioma and metastatic brain tumors compared with tumors inotherextracranial organs. TPase activity in normal brain was much less than in normal tissues in extracranialorgans and its activity in gray matter (cortex) was significantly lower than that in white matter. Ontheother hand, TK activity in malignant brain tumors was much less than that in extracranial organs,howev-er, its activity in normal brain was almost equal to that in normal tissues in extracranial organs. Thesedataobtained in vivo study showed FdUrd to be a possible agent for intrathecal chemotherapy.