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Vol. 55, Issue 3, 515-520, March 1999

Comparison of the Mechanism of Cytotoxicity of 2-Chloro-9-(2-deoxy-2-fluoro-beta -D-arabinofuranosyl)adenine, 2-Chloro-9-(2-deoxy-2-fluoro-beta -D-ribofuranosyl)adenine, and 2-Chloro-9-(2-deoxy-2,2-difluoro-beta -D-ribofuranosyl)adenine in CEM Cells

William B. Parker, Sue C. Shaddix, Lucy M. Rose, Donna S. Shewach, Larry W. Hertel, John A. Secrist, III, John A. Montgomery, and L. Lee Bennett, Jr.

Southern Research Institute, Birmingham, Alabama (W.B.P., S.C.S., L.M.R., J.A.S., J.A.M., L.L.B.); Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan (D.S.S.); and Lilly Research Laboratories, Indianapolis, Indiana (L.W.H.)

In an effort to understand biochemical features that are important to the selective antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta -D-arabinofuranosyl)adenine [Cl-F(up-arrow )-dAdo], we evaluated the biochemical pharmacology of three structurally similar compounds that have quite different antitumor activities. Cl-F(up-arrow )-dAdo was 50-fold more potent as an inhibitor of CEM cell growth than were either 2-chloro-9-(2-deoxy-2-fluoro-beta -D-ribofuranosyl)adenine [Cl-F(down-arrow )-dAdo] or 2-chloro-9-(2-deoxy-2,2-difluoro-beta -D-ribofuranosyl)adenine [Cl-diF(up-arrow down-arrow )-dAdo]. The compounds were similar as substrates of deoxycytidine kinase. Similar amounts of their respective triphosphates accumulated in CEM cells, and the rate of disappearance of these metabolites was also similar. Cl-F(up-arrow )-dAdo was 10- to 30-fold more potent in its ability to inhibit the incorporation of cytidine into deoxycytidine nucleotides than either Cl-F(down-arrow )-dAdo or Cl-diF(up-arrow down-arrow )-dAdo, respectively, which indicated that ribonucleotide reductase was differentially inhibited by these three compounds. Thus, the differences in the cytotoxicity of these agents toward CEM cells were not related to quantitative differences in the phosphorylation of these agents to active forms but can mostly be accounted for by differences in the inhibition of ribonucleotide reductase activity. Furthermore, the inhibition of RNA and protein synthesis by Cl-F(down-arrow )-dAdo and Cl-diF(up-arrow down-arrow )-dAdo at concentrations similar to those required for the inhibition of DNA synthesis can help explain the poor antitumor selectivity of these two agents because all cells require RNA and protein synthesis.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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