title: Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations of N4-alkyl derivatives of 1-beta-D-arabinofuranosylcytosine.
abstract: The oral cytostatic activity in L1210 mouse leukaemia of the two new N4-alkyl derivatives of 1-beta-D-arabinofuranosylcytosine (AraC), N4-hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NH-AraC, NO-AraC) was investigated. In contrast to AraC, both derivatives were highly cytostatic after oral application as liposome formulations. With treatment schedules of five consecutive dosages or with two applications on days 1 and 4 after intravenous tumour cell inoculation with a total dose of 470-1000 mg/kg NH-AraC or NO-AraC, 70%-100% of the treated animals were cured. The lethal dose in healthy ICR mice after a single intraperitoneal application, corresponding to the LD50, was 524 mg/kg for NO-AraC, whereas NH-AraC proved to be less toxic. The haematological toxicity remained moderate for both drugs with a mild leucopenia and a drop in platelet counts, which recovered 4-6 days after treatment. The erythrocytes were not affected and haemolytic toxicities were absent. As non-haematological toxicities, at high drug concentrations, a pronounced atrophy of the rapidly dividing epithelia of the small intestines and of the white pulp of the spleen were observed. The blood levels of NH-AraC given orally reached values comparable to those after parenteral application of a four-times lower dose of NH-AraC, suggesting a moderate bioavailability. Thus, these two lipophilic derivatives of AraC are compounds with a potential for the oral treatment of malignant diseases.
authors.affiliation: Department of Internal Medicine, University Hospital, Zürich, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: D H
authors.initials: DH
authors.lastname: Horber
authors.forename: B
authors.initials: B
authors.lastname: Odermatt
authors.forename: H
authors.initials: H
authors.lastname: Schott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D003561:Cytarabine; C074701:N(4)-hexadecyl-1-arabinofuranosylcytosine; C098086:N(4)-octadecyl-1-arabinofuranosylcytosine