Arterial Infusion Chemotherapy Combined with Calcium Antagonist for Advanced Hepatic Malignancies : Experimental and Clinical Study

摘要

【目的】カルシウム (以下, Ca) 拮抗剤がP-糖蛋白質の関与する抗癌剤の耐性機構を阻害し, 抗腫瘍効果を増強させ, また, 肝で不活化されることに着目し, Ca拮抗剤併用肝動注療法の有用性を実験的, 臨床的に検討した。【対象および方法】実験 : 家兎VX2腫瘍の肝転移モデル16羽を用いた。Ca拮抗剤は verapamil (VER) 1.5mg/kg, 抗癌剤は adriamycin (ADM) 1mg/kgを肝動注し, 腫瘍組織内ADM濃度をADM単独動注群とVER併用動注群で比較した。臨床 : 肝細胞癌患者10人にVER0.5mg/kgを固有肝動脈内注入し, 経時的な血中VER濃度測定とDSAの time-density curve の解析を行い, VERの至適投与量および肝動脈の血流分布の変化を検討した。臨床応用例は高度進行肝細胞癌8例で, VER0.4～0.5mg/kgおよびADM10～20mgをリザーバーより動注した。【結果】実験 : 腫瘍組織内ADM濃度は, 単独動注群に比べADMの動注直後にVERを動注した群で高い傾向がみられた。病理組織学的検討によりVERの投与の安全性が確認された。臨床 : 末梢血中濃度は至適濃度範囲内であり, 循環器系への重篤な副作用はみられなかった。VERの動注後の腫瘍部への血流量は減少した。8例中7例に画像上NCを維持でき, 3例に腫瘍マーカーの低下あるいは平坦化を認めた。また, 従来のADM単独動注と比べ, 生存期間の延長が認められた。【結語】本法は安全で, 抗癌剤に耐性を獲得した高度進行肝癌に対して有効と考えられた。 / Purpose Calcium (Ca) antagonist suppresses the multidrug resistant mechanism induced by P-glycoprotein and enhances anticancer effect resultantly. Systemic concentration of Ca antagonist after hepatic arterial infusion is expected to be minimum because it is mainly metabolized by the liver. We applied this action of Ca antagonist to the hepatic arterial infusion chemotherapy for hepatic malignancies experimentally and clinically. Methods and Materials A) Experimental study : 1.5mg/Kg of verapamil (VER) and 1.0mg of adriamycin (ADM) were infused via hepatic artery for multiple hepatic VX 2 tumors of 16 rabbits. The effect of order of administration of VER on tissue concentration of ADM was studied. Tissue concentration of ADM and were investigated. B) Clinical study : Pharmacokinetics and vasodilation effect of VER on tumor blood circulation were investigated in ten patients with HCC. We treated eight patients with far advanced HCC by arterial infusion chemtherapy (ADM : 10mg/body) combination with large volume of VER (0.5mg/kg) via implantable port. Results A) Experimetal study : The level of tissue ADM concentration of tumors was the highest in the group of VER administration immediately after ADM infusion. No remakable change in the main organs were shown pathologically. B) Clinical study : Serum VER concentration were within optimum range. No severe side effects on circulatory system were observed. On DSA examination, blood flow into the tumor reduced after infusion of VER. NC were gained in 7 of 8 patients as for the primary effect for the tumors, and decrease or plateau in alteration of tumor markers level were observed in three patients. Longer median survival term was shown compared with that without VER. Conclusion Hepatic arterial infusion chemotherapy combination with 5 times as usual amount of VER was safe and expected to be effective experimentally and clinically.