Antitumor characteristics of the conjugate of N4-(4-carboxybutyryl)-ara-C with ethylenediamine-introduced dextran and its resistance to cytidine deaminase.

Abstract

By oxidation of dextran, and reduction of the Schiff bases formed by reaction of the oxidised dextran with diaminoalkanes, several diaminoalkane-introduced dextrans were prepared and evaluated as drug carriers. Conjugates between N4-(4-carboxyburyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C) and such drug carriers were prepared, and selected conjugates were tested in vivo, and investigated for inhibitory effects on cytidine deaminase. Ethylenediamine-introduced dextran prepared under 10% oxidation conditions was found to be most useful as a drug carrier from its chemical characteristics and toxicity evaluation in BDF1 mice. The conjugate obtained from glu-ara-C and ethylenediamine-introduced dextran 2000 showed high antitumor activity, significant at the relatively low dose of 100 mg equivalent ara-C/kg, in BDF1 mice bearing L1210 leukemia cells. Glu-ara-C and the conjugate were unaffected by cytidine deaminase under conditions in which 1-beta-D-arabinofuranosylcytosine was degraded rapidly to 1-beta-D-arabinofuranosyluracil.