Antitumor Activity and Pharmacology of 1‐β‐D‐Arabinofuranosylcytosine‐5′‐stearylphosphate: An Orally Active Derivative of 1‐β‐D‐Arabinofuranosylcytosine

The antitumor activity of l‐β‐D‐arabinofuranosylcytosine‐5′‐alkylphosphates (CnPCAs) against L1210 leukemia in mice after oral administration was demonstrated. The optimum length of the alkyl group on the phosphate moiety of CnPCA for exhibiting a high antitumor activity was found to be between tetradecyl (C14) and tricosyl (C23). The most active alkyl derivative in this system was found to be l‐β‐D‐arabinofuranosylcytosine‐5′‐stearylphosphate (C18PCA). The optimum and minimum effective doses of C18PCA were 100 and 6,25 mg/kg/day (q1d, day 1 to day 5), respectively. The maximum T/C% of C18PCA was approximately 220. The antitumor activity of C18PCA was not greatly dependent on the treatment schedule and route. Plasma concentration of 1‐β‐D‐arabinofurano‐sylcytosine (ara‐C) remained in the range of 0.4 to 0.75 μmol/ml for 24 h after oral administration of 100 mgAg (170 μmol/kg) of C18PCA. These results indicate that C18PCA administered per orally is absorbed intact through the gastrointestinal tract and ara‐C is released for a long period of time. C18PCA is regarded as an orally active depot form of ara‐C