Antitumor activity and pharmacology of 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate: an orally active derivative of 1-beta-D-arabinofuranosylcytosine.

The antitumor activity of 1-beta-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 1-beta-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-beta-D-arabinofuranosylcytosine (ara-C) remained in the range of 0.4 to 0.75 nmol/ml [corrected] for 24 h after oral administration of 100 mg/kg (170 mumol/kg) of C18PCA. These results indicate that C18PCA administered per orally is absorbed intact through the gastrointestinal tract and area-C is released of long period of time. C18PCA is regarded as an orally active depot form of ara-C.

l‐β‐D‐arabinofuranosylcytosine

1‐β‐D‐arabinofuranosyluracil

l‐β‐D‐arabino‐furanosylcytosine‐5′‐monophosphate

l‐β‐D‐arabino‐furanosylcytosine‐5′‐alkylphosphate

1‐β‐D‐arabino‐furanosylcytosine‐5′‐stearylphosphate, 4‐amino‐1 ‐β‐D‐arabino‐furanosyI‐2 (1H)‐pyrimidinone 5′‐(octadecyl hydrogen phosphate)

N4‐palmitoyl‐l‐β‐D‐arabinofuranosylcytosine