ORAL ANTILYMPHOCYTE ACTIVITY AND INDUCTION OF APOPTOSIS BY 2-CHLORO-2'-ARABINO-FLUORO-2'-DEOXYADENOSINE

Citation
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
Citations number
31
ISSN journal
00278424
Volume
89
Issue
7
Year of publication
1992
Pages
2970 - 2974
Database
ISI
SICI code
0027-8424(1992)89:7<2970:OAAAIO>2.0.ZU;2-W
Abstract
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 .