Phospholipid derivatives of nucleoside analogs as prodrugs with enhanced catabolic stability.
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.
D000818:Animals; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003567:Cytidine Diphosphate Diglycerides / Q000008:administration & dosage; D003641:Deamination; D003692:Delayed-Action Preparations; D007274:Injections, Intraperitoneal; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D011379:Prognosis; D012263:Ribonucleosides / Q000008:administration & dosage*; D013678:Technology, Pharmaceutical; D014372:Tubercidin / Q000008:administration & dosage* / Q000031:analogs & derivatives; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D003567:Cytidine Diphosphate Diglycerides; D003692:Delayed-Action Preparations; D012263:Ribonucleosides; D003561:Cytarabine; C018457:1 beta-D-arabinofuranosylcytosine 5'-diphosphate-L-1,2 dipalmitin; C031400:9 beta-D-arabinofuranosyladenine 5'-diphosphate-5'-1,2-dipalmitin; C031199:tubercidin 5'-diphosphate-5'-1,2-dipalmitin; D014740:Vidarabine; D014372:Tubercidin