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Biochemical Effects of 2'-Fluoro-5-methyl-1-ß-D-arabinofuranosyluracil and 2'-Fluoro-5-iodo-1-ß-D-arabinofuranosylcytosine in Mouse Leukemic Cells Sensitive and Resistant to 1-ß-D-Arabinofuranosylcytosine¹

Laboratories of Pharmacology [T-C. C., T. J. B., F. S. P.], Applied Therapy [J. H. B.], Experimental Antitumor Testing [F. A. S.], and Organic Chemistry [T-L. S., K. A. W., J. J. F.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

2'-Fluoro-5-methyl-1-ß-D-arabinofuranosyluracil (FMAU), like 2'-fluoro-5-iodo-1-ß-D-arabinofuranosylcytosine (FIAC), has potent antiviral activity, but unlike FIAC, it also has antileukemic effects. The two agents and 1-ß-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-ß-D-arabinofuranosyluracil and 2'-fluoro-5-ethyl-1-ß-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.

² To whom requests for reprints should be addressed.

Received 1/28/82. Accepted 6/29/82.

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