The in vitro toxicities of 19 analogues of
deoxyadenosine were tested using a panel of human
melanoma cell lines including two lines sensitive to
deoxyadenosine and
deoxyinosine. The 2-fluoro-, 2-chloro-, 2-bromo- and 2-amino-8-aza derivatives were the most toxic and showed selectivity against
deoxyadenosine-sensitive cells. 2-Bromodeoxyadenosine (
BrdAdo) and its 5'-phosphate were less potent than the chloro compound but showed the greatest selectivity. In further studies of
BrdAdo a third sensitive
melanoma line was identified of the eight tested. A treatment time of 24 hr or more was required to develop toxicity to BrAdo; this could be prevented by
deoxycytidine or
cytidine added to the medium but not by other
nucleosides. Flow cytometry showed that
BrdAdo blocked cells in the G1 and S phases of the cell cycle.
DNA synthesis as judged by
thymidine incorporation was rapidly inhibited by
BrdAdo to an extent which reflected the sensitivity of the particular cell line;
RNA synthesis was less affected. Exposure to
BrdAdo for 48 hr induced breaks in the preformed
DNA of sensitive but not resistant cells. The results suggest that the toxicity of
BrdAdo is associated with prolonged inhibition of
DNA synthesis and subsequent DNA fragmentation.