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今回,tumor dormancyを目的とした化学療法として,CPT-11の低用量投与法を試みた.低用量投与としては,25mg/m^2をday1,2,3/wで毎週継続するレジメとした.対象は,転移性胃癌と大腸癌,それぞれ8例,計16例である.その結果,低用量投与では副作用が激減し,grade3以上の骨髄抑制を3例(18.6%)をみるのみであった.また投与期間は著明に延長し,平均7.1月で従来法1.8月の約4倍にも相当した.抗腫瘍効果では,奏効率が50%と従来法の29.4%と大きな差は認められなかったが,time to progression (TTP)では,低用量群では平均5.3月と,従来法群の1.6月と3倍以上の差が認められた.またmedian survival time (MST)もそれぞれ11.5月,4.5月と有意差が認められた.以上本法は,縮小よりもTTPの延長から生存期間の延長をもたらす化学療法,いわゆる"dormant chemotherapy"と考えられた. We tried a new regimen with frequent administration of low-dose CPT-11 to reduce side effects without any impairing efficacy, administering 25mg/m^2 of CPT-11 continuously on days 1, 2, and 3 of each week in 8 patients with metastatic colon cancer and 8 with metastatic gastric cancer. Grade-3 marrow depression occurred in only 3 patients. Of our 16 patients, 8 had PR, 7 had NC, and 1 had PD, showing a 50% efficacy. Time to progression (TTP) averaged 5.3 months and median survival time (MST) 11.5 months, significantly superior to rusults for the conventional CPT-11 regimen. These results suggest that the low-dose CPT-11 regimen is promising and potential by reduces side eflects and strengthens the antitumor effect, inducing prolonged TTP and survival.

Despite the generally high cure rate in patients with metastatic testicular cancer, 20% to 30% of treated patients will become candidates for salvage chemotherapy. We reviewed the recent salvage chemotherapy trials of refractory diseases. CPT-11 is a new derivative of camptothecin and has activity in a variety of solid tumors. We evaluated the antitumor effect of combination chemotherapy using CDDP and CPT-11 against refractory testicular cancer. Fourteen patients who failed to achieve complete remission with salvage chemotherapy were treated with combination chemotherapy with CPT-11 and CDDP or 254-S (nedaplatin) as third line chemotherapy. Six patients remain alive and disease-free and 5 patients died of disease. The combination of CPT-11 and either CDDP or nedaplatin was significantly more effective than other salvage therapy regimens such as VIP. Paclitaxel, ifosfamide, etoposide regimens were also effective in patients with refractory testicular tumors. We concluded that these combination regimens demonstrated significant activity against refractory testicular tumor and further investigation is warranted.

51歳,男性の進展型肺小細胞癌(T2N3M1)に対しシスプラチンとエトポシドの併用化学療法を2コース施行し,引き続いて塩酸イリノデカン(以下CPT-11)を総計560mg(320mg/m2)投与した.CPT-11投与開始後7週目より乾性咳鰍と38℃台の発熱を認め,胸部レントゲン写真で両下肺野を中心にスリガラス様陰影,胸部CTでは両肺びまん性の肺野濃度上昇を認めた.臨床経過よりCPT-11による肺臓炎を疑い,静注メチルプレドニゾロンおよび経口プレドニソロンを投与し,臨床症状の軽快と胸部レントゲン写真およびCTで陰影の改善を認めた.CPT-11による薬剤性肺臓炎の報告は少ないが,今後CPT-11を投与するにあたり十分な注意と発症時の早急な対処が必要である., A 51-year-old patient with extensive small cell lung cancer was treated with a total of 560mg ( 320mg/m2 ) of irinotecan hydrochloride ( CPT-1 1 ) following two cycles of cisplatin and etoposide. In the seventh week after the start of CPT-11 therapy, the patient complained of hacking cough and exertional dyspnea with a high fever. Chest X-ray film and chest computed tomogram showed ground-glass opacity mainly in both lower lung fields. Drug-induced pneumonitis due to CPT-11 was strongly suspected, and prednisolone was orally administered and methylprednisolone was administered intravenously. After the steroid therapy, the symptoms and lung opacity gradually disappeared. Although CPT-11-induced pneumonitis is rare, oncologists should be aware of the possibility of its occurring during or following CPT-11 administration., 肺癌 = Japanese Journal of Lung Cancer, 39(1), p.57-61; 1999

51歳,男性の進展型肺小細胞癌(T2N3M1)に対しシスプラチンとエトポシドの併用化学療法を2コース施行し,引き続いて塩酸イリノデカン(以下CPT-11)を総計560mg(320mg/m2)投与した.CPT-11投与開始後7週目より乾性咳鰍と38℃台の発熱を認め,胸部レントゲン写真で両下肺野を中心にスリガラス様陰影,胸部CTでは両肺びまん性の肺野濃度上昇を認めた.臨床経過よりCPT-11による肺臓炎を疑い,静注メチルプレドニゾロンおよび経口プレドニソロンを投与し,臨床症状の軽快と胸部レントゲン写真およびCTで陰影の改善を認めた.CPT-11による薬剤性肺臓炎の報告は少ないが,今後CPT-11を投与するにあたり十分な注意と発症時の早急な対処が必要である., A 51-year-old patient with extensive small cell lung cancer was treated with a total of 560mg ( 320mg/m2 ) of irinotecan hydrochloride ( CPT-1 1 ) following two cycles of cisplatin and etoposide. In the seventh week after the start of CPT-11 therapy, the patient complained of hacking cough and exertional dyspnea with a high fever. Chest X-ray film and chest computed tomogram showed ground-glass opacity mainly in both lower lung fields. Drug-induced pneumonitis due to CPT-11 was strongly suspected, and prednisolone was orally administered and methylprednisolone was administered intravenously. After the steroid therapy, the symptoms and lung opacity gradually disappeared. Although CPT-11-induced pneumonitis is rare, oncologists should be aware of the possibility of its occurring during or following CPT-11 administration.

ヌードマウス可移植ヒト精巣腫瘍株を用い, CPT-11とCDDPなどのプラチナ化合物との併用療法により, 抗腫瘍効果の著しい増強がみられることを示した。この結果をふまえ, 4例の難治性精巣腫瘍に対しCPT-11とCDDPや254-Sによる併用療法を行い, 2例でその有効性が示された, The antitumor effects of combination chemotherapies using CDDP and the camptothecin analogue CPT-11 were compared with those of vinca alkaloids or podophyllotoxins, and those of CPT-11 and cisplatinum analogues were also estimated. Two human testicular cancer xenografts (TTSC -2 and TTSC-3) heterotransplanted in nude mice were used. Combination therapy with CPT-11 and CDDP resulted in significant tumor regression and was much more effective than that of CDDP and vinca alkaloids or podophyllotoxin. The combination of CPT-11 and either CDDP or 254-S was significantly more effective than that of CPT-11 and either carboplatin or DWA2114R. Four evaluable refractory testicular cancers were treated with combination chemotherapy with CPT-11 and CDDP or 254-S as third line chemotherapy. Two patients remain alive and disease free and two patients died of disease. We concluded that the present combination is active in refractory testicular cancer.

本研究の目的はSN-38を内包ミセル化したDDS製剤であるNK012がDDS製剤の特性を生かし、悪性神経膠腫に対して抗腫瘍効果を発揮するか否かをCPT-11との比較で検討するとともに、臨床応用への可能性を探ることである。

研究科: 千葉大学大学院薬学研究院, 学位:千大院薬博甲第105号