[Fundamental studies on intravesical instillation of 4'-epi-adriamycin for the treatment of bladder cancer]

Abstract

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.