2′-Fluoro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU), like 2′-fluoro-5-iodo-1-β-d-arabinofuranosylcytosine (FIAC), has potent antiviral activity, but unlike FIAC, it also has antileukemic effects. The two agents and 1-β-d-arabinofuranosylcytosine (ara-C) are compared herein. Concentrations inhibiting thymidine (dThd) incorporation into DNA by 50% are for FMAU, FIAC, and ara-C, respectively, in L1210/0, 32, 353, and 0.2 µm and in L1210/ara-C, 17, >10,000, and 3,900 µm. Other FMAU analogs, 2′-fluoro-5-iodo-1-β-d-arabinofuranosyluracil and 2′-fluoro-5-ethyl-1-β-d-arabinofuranosyluracil, inhibit dThd incorporation equally in ara-C-sensitive and -resistant cells; however, their potencies are weaker than that of FMAU. Similar results are obtained when [3H]deoxyadenosine is used as a precursor of incorporation. In L1210/0 cells, incorporation of [2-14C]FMAU radioactivity into DNA is competitively inhibited by dThd and deoxycytidine (dCyd), whereas the incorporation of [2-14C]FIAC radioactivity is competitively inhibited by dCyd but not appreciably by dThd. In L1210/ara-C cells, incorporation of [2-14C]FMAU is competitively inhibited by dThd but not by dCyd. In L1210/0 cells, FMAU has little inhibitory effect on the tritium release from [5-3H]deoxyuridine but markedly inhibits the incorporation of [2-14C]deoxyuridine into DNA. FIAC, by contrast, predominately inhibits the release of tritium from [5-3H]deoxyuridine but has little effect on subsequent incorporation into DNA. These results suggest that (a) FIAC, but not FMAU, is cross-resistant to ara-C; (b) FMAU is particularly effective against L1210/ara-C cells; (c) FIAC behaves metabolically like dCyd, and FMAU like dThd and dCyd; (d) dCyd and dThd may be used as chemotherapeutic modulators; and (e) FIAC predominately inhibits dThd kinase and/or thymidine monophosphate synthetase, whereas FMAU predominately inhibits DNA polymerase and/or nucleotide kinases. Similar conclusions were obtained when P815/0 and P815/ara-C cells were used. The relative potencies of FIAC and FMAU in inhbiting dThd incorporation into DNA in leukemic sublines correlate with cytotoxicity in vitro and chemotherapeutic effects in vivo.

1

This work was supported by National Cancer Institute Grants CA 27569, CA 18856, CA 08748, CA 18601, and CA 09207 and by the Elsa U. Pardee Foundation.

This content is only available via PDF.