Evaluation of the conjugate between N4-(4-carboxybutyryl)-1-beta-D-arabinofuranosylcytosine and chitosan as a macromolecular prodrug of 1-beta-D-arabinofuranosylcytosine.
The conjugate of N4-(4-carboxybutyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C) with chitosan, named chi-glu-ara-C, was prepared and evaluated on its utility as a macromolecular prodrug. 1-beta-D-Arabinofuranosylcytosine (ara-C) was predominantly regenerated gradually from chi-glu-ara-C in 1/15 M phosphate buffer, pH 7.4, at 37 degrees C, and its amount after 7 d incubation was 56% (w/w). The antitumor effect was evaluated by an increase in the lifespan (ILS) of the mice bearing P388 leukemia at the single administration at 24 h after inoculation. Ara-C exhibited an ILS of 3.4% at a dose of 100 mg/kg, and the survival time was not significantly different from that of the control. However, chi-glu-ara-C showed an ILS of 60.7% at a dose of 88 mg eq ara-C/kg, and the survival time was significantly different from that of the control. Chitosan and chi-glu-ara-C were observed to cause the side effects judged from the body weight loss to a certain extent. However, chi-glu-ara-C was recognized to be useful because of its effectiveness.
Ichikawa
H
H
Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Onishi
H
H
Takahata
T
T
Machida
Y
Y
Nagai
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002686:Chitin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D048271:Chitosan; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration; D007941:Leukemia P388 / Q000188:drug therapy; D008136:Longevity / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000138:chemical synthesis*; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011355:Prodrugs; C086695:chitosan-N(4)-(4-carboxybutyryl)-1-arabinofuranosylcytosine conjugate; D003561:Cytarabine; D002686:Chitin; C068236:N(4)-(4-carboxybutyryl)-1-beta-arabinofuranosylcytosine; D048271:Chitosan