2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells
Z Spigelman, R Duff, GP Beardsley, S Broder, D Cooney, NR Landau, H Mitsuya, B Ullman and R McCaffrey
Evans Department of Clinical Research, Boston University Medical Center, MA
02118.
The 2',3'-dideoxynucleosides (ddNs) are currently undergoing clinical
evaluation as antiretroviral agents in HIV-infected individuals. When
phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate
analogues with reverse transcriptase, thereby inhibiting HIV replication.
These nucleoside analogues can also inhibit, by chain- terminating
additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl
transferase (TdT). To determine the effect of possible intracellular
chain-terminating additions of ddNMPs by TdT, we exposed a series of
TdT-positive and TdT-negative cell lines to 2',3'- dideoxyadenosine (ddA),
a representative ddN. At ddA concentrations 25- fold higher than required
for inhibition of HIV replication, progressive dose-related cytotoxicity
was observed in the TdT-positive cell lines. This was accentuated by the
adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the
intracellular generation of ddATP from ddA. A central role of TdT in
mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell
line rendered TdT positive by infection with a TdT cDNA-containing
retroviral vector. After a 48-hour continuous exposure period to 250
mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the
TdT-negative parental line, whereas 90% cell death was observed in the
TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells
to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute
lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic
cells (six cases). We conclude that ddA/CF selectively damages TdT-positive
cells, presumably by chain-terminating additions of ddAMP, and that this
may have therapeutic relevance in TdT-positive malignant disease.
Volume 71,
Issue 6,
pp. 1601-1608,
06/01/1988
Copyright © 1988 by The American Society of Hematology
