ヌードマウス可移植ヒト腎細胞癌に対する各種抗癌剤の抗腫瘍効果
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当教室で継代維持しているヌードマウス可移植ヒト腎細胞癌のうち,原腫瘍の組織学的特徴をよく保持し,かつ増殖の安定した2株を用い,各種抗癌剤の感受性試験を行い,腫瘍増殖曲線および組織学的所見の変化に基づいて抗腫瘍効果を検討した.腫瘍増殖曲線からみて,推計学的に有意な増殖抑制効果がみられたものは,AM-RC-1株においてはMMC 3 mg/kg群のみであった.ADM 5 mg/kg群では2回目投与時点で増殖抑制効果がみられたが,最終投与後に強い急性毒性が出現し,有意差検定ができなかった.AM-RC-6においてもMMC 3 mg/kg群のみが有意な増殖抑制効果を示した.光顕レベルでの検討では,AM-RC-1ではMMC 3 mg/kg群において,腫瘍細胞の細胞質の膨化,空胞化が著明で,核の濃縮,膨化,空胞化,核崩壊,核膜過染,核溶解などが広汎に認められたが,他の投与群では悪化はほとんど無くgrade 0～1であった.一方AM-RC-6では著明な変性所見を示した抗癌剤は全く見られず,すべてgrade 0～1の変化であった.電顕所見では,AM-RC-1はMMC 3 mg/kg群において,細胞質内小器官の空胞の増加が目立ち,腺腔内にdebrisが大量充満していた.ADM投与群では5 mg/kg群において,腺腔内にdebrisの貯留がみられたが,細胞質内小器官の変化は少なかった.CDDP投与群では5.6 mg/kgおよび2.8 mg/kgの両群において,細胞質内にautophagic vacuoleが散見し,間質に膠原線維の増生が見られたが,細胞質内小器官の変化はほとんど認められなかった.AM-RC-6ではMMC 3 mg/kg群において,細胞質内に軽度の空胞変性がみられ,またADM 5 mg/kg群,CDDP 5.6 mg/kg, 2.8 mg/kg群において,細胞質にwatery degenerationが認められた.腫瘍増殖曲線による増殖抑制効果と組織学的変化は,AM-RC-6に対するMMC 8 mg/kg群を除いてよく一致したUsing two xenografts of human renal cell carcinomas serially transplanted in nude mice (AM-RC-1 and AM-RC-6), both of which maintained the basic histologic features of the original tumor and showed a constant growth rate, the effects of various anticancer agents against 2 target tumors were evaluated. MitomycinC (MMC), adriamycin (ADM), cisplatinum diaminodichloride (CDDP), 5-fluorouracil (5FU), 5-fluro-2'-deoxy-beta-uridine (FUDR) and human lymphoblastoid interferon (HLBI) against AM-RC-1, and MMC, ADM, CDDP, vinblastin (VBL) and etoposide (VP-16) against AM-RC-6. Drugs other than HLBI were administered 3 times in total every three to five days by intraperitoneal injection according to Battelle Columbus Laboratories Protocol and HLBI was injected daily for 10 days intraperitoneally. Anti-cancer effects were evaluated based on tumor growth curve and changes of histologic findings. In terms of tumor growth only MMC (in a dose of 3 mg/kg) revealed a statistically significant inhibitory effect against both AM-RC-1 and AM-RC-6 (respectively P less than 0.001 and P less than 0.05). Concerning AM-RC-1, a significant difference (P less than 0.01) was recognized in the ADM group (5 mg/kg) at the time of the second administration, but evaluation could not ultimately be done owing to appearance of acute toxity after the last dose. The most remarkable histologic changes by light microscopy were recognized in the MMC group (in a dose of 3 mg/kg) against AM-RC-1. They were degenerative findings such as intracellular and nuclear vacuolation, karyorrhexis, karyolysis, karyopyknosis and marginal hyperchromatosis, which corresponded to grade IIa of the classification of the National Cancer Center. The other drugs administered to AM-RC-1 exhibited only grade O to grade I changes. On the other hand, in AM-RC-6, histologic changes were mild (less than grade II) for all the drugs. Electron microscopic features were as follows. AM-RC-1: Marked increase of vacuole of organella was observed and lumens were filled with a large quantity of debris in MMC group (3 mg/kg). In the ADM group (5 mg/kg) there was debris in lumens, although almost no changes of organella were seen. CDDP groups (both 5.6 mg/kg and 2.8 mg/kg) showed autophagic vacuole in the cytoplasm and increased collagen fibers in the stroma but little changes of organella. AM-RC-6: Mild intracellular vacuolation was recognized in the MMC group (3 mg/kg). Watery degeneration and microfibrils were found in the cytoplasm in both ADM (5 mg/kg) and CDDP (5.6 mg/kg, 2.8 mg/kg) groups.
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