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• W1496100144 abstract "The pharmacological properties of the new anthracycline, 3′-morpholino-3′-deaminodaunorubicin (MD), and Adriamycin (ADR) have been compared in human colon carcinoma (HT-29) cells in vitro . ADR was 10-fold more cytocidal than MD to log-phase cells upon short (2 hr)- or long (24 hr)-term drug exposure. In plateau-phase cells, 2-hr exposure to either ADR or MD produced equivalent reductions in colony formation, but ADR was 3-fold more toxic than MD following 24-hr treatment. Although ADR produced greater cell lethality than MD, the latter drug was far more inhibitory to DNA and RNA synthesis at equitoxic concentrations.This disparity was related to pharmacodynamic differences between the two drugs. The cellular uptake of MD was rapid and reached a plateau after 1 to 2 hr, whereas ADR was taken up at a 15-fold slower rate. However, by 24 hr after drug treatment, the intracellular concentration of MD decreased while ADR continued to accumulate until it reached one-half of the intracellular concentration of MD. When cells were incubated with 10−6 m drug for 24 hr, 65% of MD but less than 10% of ADR was converted to the alcohol metabolite. The fraction of metabolite was higher in the media than in the cells, demonstrating that it was less able to accumulate in the cells than the parent drug, and hence accounted for the decline in intracellular levels of MD at 24 hr. When placed in drug-free media, the rate of efflux of MD was much greater ( t ½ 45 min) than that of ADR ( t ½ 6 hr). The strikingly different pharmacodynamic properties of these drugs related to the greater lipid solubility of MD versus ADR but not to their binding affinities to DNA, which were similar. The decreased cytotoxicity of MD versus ADR was unrelated to either its metabolism, its rapid uptake and efflux, or its inhibitory effects on nucleic acid synthesis." @default.
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• W1496100144 date "1983-03-01" @default.
• W1496100144 modified "2023-09-23" @default.
• W1496100144 title "Pharmacological studies of 3'-(4-morpholinyl)-3'-deaminodaunorubicin in human colon carcinoma cells in vitro." @default.
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