Da. Carson et al., ORAL ANTILYMPHOCYTE ACTIVITY AND INDUCTION OF APOPTOSIS BY 2-CHLORO-2'-ARABINO-FLUORO-2'-DEOXYADENOSINE, Proceedings of the National Academy of Sciences of the United Statesof America, 89(7), 1992, pp. 2970-2974
2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia
, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum
of activity may be attributable to the selective toxicity of CdA to n
ondividing lymphocytes and monocytes. However, CdA is unstable at acid
ic pH and is degraded by bacterial nucleoside phosphorylases. The pres
ent experiments demonstrate that the 2'-arabino-fluoro derivative of C
dA, designated CAFdA, is also directly toxic to quiescent lymphocytes
and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted deg
radation by Escherichia coli nucleoside phosphorylase. Cell killing wa
s preceded by the formation of DNA strand breaks and could be prevente
d by supplementation of the medium with deoxycytidine. The initial DNA
damage initiated the pattern of oligonucleosomal DNA fragmentation ch
aracteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycyti
dine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expand
ed deoxynucleotide pools secondary to increased ribonucleotide reducta
se activity, were cross-resistant to both CAFdA and CdA toxicity. One-
week oral treatment with CAFdA (1 mg/ml in drinking water) achieved an
average plasma concentration of 0.56-mu-M and eliminated 90% of chron
ic lymphocytic leukemia cells transplanted into severe combined immuno
deficiency (scid) mice. Under the same conditions, CdA was much less a
ctive. Collectively, these results suggest that CAFdA could be effecti
ve as an oral agent in indolent lymphoproliferative diseases and in au
toimmune diseases where lymphocyte and monocyte depletion is desirable
.