新しい分化誘導療法剤の開発と分化誘導療法の基礎的研究

1989 年度 実績報告書

• 研究課題/領域番号: 01010074
• 研究機関: 埼玉県立がんセンター
• 研究代表者: 穂積 本男 埼玉県立がんセンター研究所, 副所長 (50113478)
• 研究分担者: 武市 紀年 北海道大学, 医学部, 助教授 (40002133) ; 水野 左敏 国立予防衛生研究所, 抗生物質部, 部長 (60072930) ; 斎藤 政樹 自治医科大学, 医学部, 教授 (60012762) ; 須田 立雄 昭和大学, 歯学部, 教授 (90014034) ; 高久 史麿 東京大学, 医学部, 教授 (40048955)
• キーワード: 分化誘導療法 / D因子 / アルキルエーテル非燐脂質 / 分化誘導療法補強剤 / シアロ糖化合物 / 熱ショック蛋白質 / 倍数性骨髄性白血病株細胞 / 活性化酸素

研究概要

分化誘導療法開発のために臨床応用可能な新規分化誘導剤を検索し、分化誘導剤の臨床応用への基礎的諸条件を検討して次の研究成果を得た。 1.新規分化誘導剤の開発:骨髄性白血病細胞(M1)蛋白質性分化誘導因子(D因子)の遺伝子をクローニングし、組換えD因子の生産に成功した(穂積)。また、新規化学合成アルキルエーテル非燐脂質が前骨髄球性白血病細胞に対して強い分化誘導と増殖抑制活性を示すことを見出した(穂積)。 2.分化誘導療法補強剤の開発:TGFーβおよびステロイドホルモンとTNFとの併用(武田)、GーCSFとレチノイン酸との併用(穂積)が骨髄性白血病細胞の分化誘導を増強すること、ハービマイシンAとNGFとの併用が褐色腫細胞の分化誘導を促進することを見出した(水野)。また、正常肺組織から単球性白血病細胞の増殖抑制因子(G1因子)が産生されることを見出し、その性質を明らかにした(穂積)。 3.分化誘導剤の作用機序:GーCSF,GM-CSF,M-CSF,IL-3が好中球および単球機能を活性化すること(高久)、D因子とILー6が骨代謝を修飾すること(須田、穂積)、シアロ糖化合物が細胞膜レセプターを介して骨髄性白血病細胞を合化誘導すること(斎藤)、癌遺伝子(cーmyc)がフレンド白血病細胞の増殖分化を制御すること(帯刀)、熱ショック蛋白質(hsp47)が胚性腫瘍細胞の分化誘導機序に関与すること(永田)を明らかにした。 4.実験動物による骨髄性白血病分化誘導療法の基礎的検討:マウスの倍数性骨髄性白血病株細胞(LLー2)を樹立し、この細胞を用いてin vivoの分化誘導剤に対する反応性と分化誘導剤による白血病マウスの治療効果を明らかにした。また、分化誘導剤耐性のラット骨髄性白血病細胞が宿主マクロファージ由来の活性化酸素によって分化し、増殖が抑制されることを確認した。

研究成果

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