The
nucleoside 5'-diphosphate-L-1,2-dipalmitin derivatives of 1-beta-D-arabinofuranosylcytosine (
ara-C),
9-beta-D-arabinofuranosyladenine (
ara-A), and
tubercidin have been synthesized, and their cytotoxicity has been evaluated against a mouse myeloma cell line (MPC-11) in vitro and against L1210
lymphoid leukemia both in vitro and in vivo. Sonication methods were utilized to solubilize these lipophilic derivatives in aqueous
solution in order to facilitate such
biological evaluation; the
ara-A derivative resisted solubilization by several techniques. The
nucleoside:
phospholipid conjugates of
ara-C and
tubercidin both were cytotoxic towards the two cell lines, and detailed experiments were cytotoxic towards the two cell lines, and detailed experiments were carried out to show that the new derivatives (a) were not degraded in the medium prior to cellular uptake and (b) acted as
prodrugs or molecular depots of the parent
nucleoside analog. In addition, 1-beta-D-arabinofuranosylcytosine 5'-diphosphate'5'-L-1,2-dipalmitin was not a substrate for
cytidine deaminase (
cytidine aminohydrolase, EC 3.5.4.5), the primary
enzyme responsible for the rapid catabolism of
ara-C. In in vivo studies against L1210
lymphoid leukemia in mice, the 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin showed an increased efficacy (increased life span, 260%) relative to the parent
ara-C (increased life span, 89%) regardless of treatment schedule used, whereas the
tubercidin 5'-diphosphate-5'-L-1,2-dipalmitin appeared extremely toxic even at low dosages. That 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin was acting as a sustained release drug in vivo was demonstrated by utilizing a single dose administered on Days -1, 0, +1, and +2 relative to inoculation of the L1210
lymphoid leukemia cells on Day 0. Again, a much increased efficacy relative to the best treatment using
ara-C was apparent. The potential advantages and the biochemical rationale for the development of these novel
prodrugs are discussed.