The Effects of 1-β-D-Arabinofuranosylcytosine and Adriamycin on the Chromosomes of Cultured Human Lymphocytes

Abstract

A study of chromosome aberrations induced by 1-β-D-arabinofuranosylcytosine (Ara C) and Adriamycin (AM) in the chromosomes of cultured human lymphocytes was made. There were significant increases in the frequency of aberrations with increasing concentrations of both Ara C (2.5, 5.0 and 10.0 μg/ml) and AM (0.01, 0.05, 0.10 and 0.15 μg/ml). The frequency of aberrations induced by both drugs also showed a 'levelling off' above particular concentrations. For Ara C the effect of increasing treatment time was also studied. The frequency of aberrations increased significantly with increasing treatment times (2, 3 and 4 hrs) although no 'levelling off’ in the number of aberrations was observed. The relationship between the frequency of the different types of aberrations induced by Ara C and AM was studied. AM allowed for a study of the relative frequency of chromosome versus chromatid aberrations and fragment versus exchange aberrations. There were always more fragments than exchanges, and always more chromatid aberrations than chromosome aberrations. Aberrations induced by Ara C were all of the chromatid fragment type. A study was made of the distribution of inter- and intra-chromosomal aberrations in relation to light and dark G banded chromosomes. Both drugs induced more aberrations in the light G bands than the dark G bands. Both drugs showed distinct clustering of aberrations in some regions of the chromosomes (hotspots), although the location of AM induced hotspots was different from the location of those induced by Ara C. The distribution of AM induced chromatid aberrations was different from the distribution of the chromosome aberrations, as were the distributions of the fragment and exchange aberrations. The different types of aberrations also differed in the number of AM induced aberrations per unit length between the p and q arms. There were more aberrations per unit length in the p arm than in the q arm for exchanges, whereas for fragments and chromosome aberrations the reverse was true. For chromatid aberrations, there was no significant difference in the number of aberrations per unit length between the p and q arms. Inter-individual differences in the frequency of AM induced aberrations were observed in the .AM dosage experiments. Also there was a suggestion that the distribution of Ara C induced aberrations was different for different donors. AM increased the frequency of sister chromatid exchanges. Comparable results were not sought for Ara C because after cells were exposed to Ara C they did not pass through an S phase of the cell cycle, as is the case for cells exposed to AM. The relevance of the present in vitro studies to cancer chemotherapy is briefly discussed.