Neurological Surgery 脳神経外科40巻6号

2012年06月発行

総説

膠芽腫に対する血管新生抑制療法のトピックス

著者： 高野晋吾¹ 松村明¹

所属機関： ¹筑波大学医学医療系脳神経外科

ページ範囲：P.481 - P.502

Ⅰ．はじめに

　腫瘍は直径が2mmを超えると血液の需要が急激に高まり，腫瘍増殖はlatent phase（潜在期）からlogarithmic phase（対数期）に移行する．したがって，これらの血管新生の促進因子を抑制，あるいは血管新生の抑制因子を増強することで血管新生のバランスを負に調節できれば，腫瘍増殖はdormant phase（休眠期）（^＊注1）に誘導され，腫瘍の増殖，進展を阻害できると考えられた．

　ベバシズマブ（抗VEGF中和抗体）の登場により，使用した膠芽腫症例では画像上，必ずといってよいほど周囲浮腫，腫瘍増強効果の軽快がみられ，ステロイドの減量によりADL（activities of daily living）の拡大がみられる．しかしながらその期間が短い場合も多く，その理由として耐性，浸潤増加での説明がされている．今後の血管新生抑制療法は，単独の抑制剤に頼らず，膠芽腫を形成する腫瘍微小環境（周皮細胞，壁細胞，マクロファージ，間質細胞，幹細胞，場合によっては周囲の正常グリア細胞）をともに制御しなければならない時代になってきている．

　もちろん，血管新生抑制療法に関しては，膠芽腫，再発膠芽腫に対してさまざまな標的分子の臨床試験が主に海外で行われているが，第Ⅲ相までの試験では，その評価方法について問題が解決できていない部分もあり，概説にとどめた．

　本稿では，

　1）腫瘍に対する血管新生抑制療法を知るためには，正常な血管新生のメカニズムを知っていることも大切であることと，最近では膠芽腫の腫瘍血管内皮細胞は正常血管内皮細胞と遺伝子学的にも違うことが明らかにされてきており，これまでの単に新生血管を抑制すればよい時代から腫瘍の内皮細胞にも合わせた治療の必要性が出てきたため，正常血管内皮細胞と腫瘍血管内皮細胞の違いを述べる．

　2）そうはいっても欧州や米国では膠芽腫に対してベバシズマブが多く使われているために，毎週といってよいほど多くの論文が発表されている．日本で使用されるときにtemozolomideの導入も既に5～10年遅れたスタートであり，日本からのデータは皆無であった．特に臨床面でのデータもであるが，実際の使用に際する副作用への対処，人種による違いを把握しておくことが，まだ日本で保険使用できない薬剤への対応として大切であると考えており，その点を述べる．

　3）ベバシズマブ単独ではなく，ベバシズマブを中心とした他の薬剤との併用療法，特に，膠芽腫細胞，腫瘍血管内皮細胞だけでなく膠芽腫微小環境（低酸素，周皮細胞，壁細胞，マクロファージ）を血管新生抑制の標的とした次世代の治療のトピックスを中心に述べる．

　したがって，これからの膠芽腫に対する血管新生抑制療法のトピックスとして，以下の8つの話題を取り上げる．

　1．腫瘍血管新生のプロセス

　2．腫瘍血管の内皮細胞は正常か？

　3．腫瘍血管新生における血管の成熟化・正常化

　4．Notchシグナルを標的とした腫瘍血管新生抑制療法

　5．膠芽腫微小環境を考えた腫瘍血管新生抑制療法（マクロファージと低酸素）

　6．膠芽腫に対する血管新生抑制療法の現状（臨床試験）：VEGF阻害による代償機構とマルチキナーゼ阻害による臨床試験

　7．膠芽腫に対する血管新生抑制療法の副作用

　8．他の癌に対するベバシズマブ療法から学べることはないか？

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