Conjugate of N4-(4-carboxybutyryl)-ara-C and ethylenediamine-introduced dextran. Drug release profiles and further in vivo study of its antitumor effects.
In vitro and further in vivo work with a conjugate formed from the cytotoxic drug 1-beta-arabinofuranosylcytosine (ara-C) and dextran 2000 are described. In the preparation of this conjugate, functionalisation of ara-C was via N4-(4-carboxybutyryl)-ara-C (glu-ara-C), permitting conjugation with amino groups introduced by prior reaction of the oxidised dextran with ethylenediamine; by varying the proportions of the reaction components, 5.4 to 7.7% w/w loadings of ara-C were obtained. At physiological pH, in vitro, drug release from a 5.4% loaded conjugate was gradual and was dominantly ara-C; at lysosomal pH (pH 5) the release rate was much slower and more ara-U was formed. Antitumour effects were evaluated in L1210 leukaemic mice following single (1 day after inoculation) or double (2 and 6 days after inoculation) intraperitoneal injection of ara-C, glu-ara-C, or a 7.7% loaded conjugate at three dose levels. In all cases, the increase in lifespan was greatest following use of the conjugate, but the differences in the effects of ara-C and the conjugate were only significant at the lowest dose level. Glu-ara-C was virtually inactive under all conditions.
Onishi
H
H
Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Seno
Y
Y
Pithayanukul
P
P
Nagai
T
T
D000818:Animals; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003911:Dextrans; D004337:Drug Carriers; D015195:Drug Design; D004341:Drug Evaluation; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains
D003911:Dextrans; D004337:Drug Carriers; D003561:Cytarabine; C068236:N(4)-(4-carboxybutyryl)-1-beta-arabinofuranosylcytosine