膀胱腫瘍に対する4'-epi-adriamycinの膀胱腔内注入療法に関する基礎的研究

Abstract

Adriamycin (ADM)の誘導体である4'-epi-adriamycin (EPI)を膀胱腔内注入療法に導入する目的で基礎的に検討した.1)人膀胱癌培養細胞株T24に対するEPIの殺細胞効果をcolony formation methodにて検討した.EPIはADMと比較してやや低い殺細胞効果を有していたが, mitomycin Cおよびaclacinomycin Aと比較して高い殺細胞効果を示した.2)ビーグル犬を用いて両側尿管皮膚瘻を施行し, 空置した膀胱腔内にEPIを注入し血中, 尿中および臓器内濃度をHPLC法にて測定した結果, EPIの膀胱壁よりの吸収量は少量であった.3)正常膀胱粘膜に対する影響について検討したが, 薬剤を6時間把持した場合, EPI 20 mg/生塩水10 mlでは, まったく変化は認められず, EPI 50 mg/生塩水10 mlでは, 粘膜の剥離が散在性に認められたのみであり, EPI 100 mg/生塩水10 mlでは粘膜下層に影響がおよんだ

4'-Epi-adriamycin (EPI) is a new derivative of adriamycin (ADM). The cytotoxic effect of EPI on the T24 cell line, an established cell line from human urinary bladder carcinoma, the distribution of the drug in blood, urine and tissues of various organs and histopathological change in the bladder mucosa in dogs following intravesical instillation of the drug, were studied. The cytotoxicity of EPI on the cultured T24 cells was examined by a colony formation method. After 2 hours exposure, EPI was slightly less cytotoxic than ADM, but showed higher cytotoxicity than mitomycin C or aclacinomycin A. The drug levels in blood, urine and tissues were measured by HPLC following bladder instillation in Beagle dogs with bilateral cutaneous ureterostomy. They were elevated in proportion to the drug concentration instilled intravesically. After 50 mg of EPI dissolved in 10 ml of physiological saline was instilled intravesically, the blood levels of EPI were not elevated significantly and reached the maximum levels of only 0.222 microgram/ml. The total amount of EPI excreted into the urine during the 10 hours after instillation was 389 micrograms which was equivalent to 0.78% of instilled EPI. The tissue levels of 50 mg of EPI after 6 hours retention were 1216 +/- 1094 micrograms/g in the bladder mucosa, 259 +/- 250 micrograms/g in the bladder muscular layer, 7.65 +/- 1.19 micrograms/g in the iliac node, 22.1 +/- 4.8 micrograms/g in the cortex of kidney, 15.1 +/- 3.8 micrograms/g in the medulla of kidney, 11.3 +/- 1.0 micrograms/g in liver and 5.80 +/- 1.20 micrograms/g in the heart. To examine the effect of the drug on the bladder mucosa, 50 mg of EPI was instilled intravesically. After 6 hours retention, bladder mucosa was observed through a microscope and a scanning electron microscope. Only exfoliation in the mucosa was observed sporadically and no histological change was observed in the submucosal layer. The above results suggest that EPI is a suitable drug for intravesical chemotherapy to bladder cancers.