title: Lipophilic 1-beta-D-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model.
abstract: The N4-alkylcytosine arabinoside derivative N4-octadecyl-AraC (AraC-Ocd, NOAC) and the (1-octadecylglycero-3-phospho)-AraC (Ocd-GroP-AraC, OPA) conjugate are new lipophilic derivatives of the cytostatic drug 1-beta-D-arabinofuranosylcytosine (AraC) that produce high antileukemic effects in the L1210 murine leukemia model when administered orally or parenterally as liposomal formulations. Between 83% and 100% of the treated animals were cured after five consecutive daily oral drug applications with a total dose of 1 mmol/kg AraC-Ocd or Ocd-GroP-AraC. Corresponding results were obtained after parenteral therapy on days 2 and 6 after tumor inoculation with five- to ten-fold lower concentrations of these two compounds. A comparable cytotoxic activity was found with the orally active AraC-5'-(n-stearyl phosphate). However, because of its strong hemolytic toxicity this derivative cannot be used for parenteral therapy. Another AraC conjugate, which was modified with two long-chain hydrocarbons, the (1-octadecylglycero-3-phospho)-N4-hexadecyl-AraC was, probably because of poor oral bioavailability, only active when applied parenterally. The new lipophilic AraC derivatives AraC-Ocd and Ocd-GroP-AraC are compounds with a high potential for the oral treatment of leukemias and possibly also of solid tumors.
authors.affiliation: Department of Pathology, University Hospital, Zürich, Switzerland. onkschwn@usz.unizh.ch
authors.forename: R A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: H
authors.initials: H
authors.lastname: Schott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D005260:Female; D007263:Infusions, Parenteral; D007939:Leukemia L1210 / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship
chemical_list: D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D003561:Cytarabine