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
Wb. Parker et al., 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, MOLEC PHARM, 55(3), 1999, pp. 515-520
In an effort to understand biochemical features that are important to the s
elective antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinof
uranosyl)adenine [CI-F(up arrow)-dAdo], we evaluated the biochemical pharma
cology of three structurally similar compounds that have quite different an
titumor activities. CI-F(up arrow)-dAdo was 50-fold more potent as an inhib
itor of CEM cell growth than were either 2-chloro-9-(2-deoxy-2-fluoro-beta-
D-ribofuranosyl)adenine [CI-F(down arrow)-dAdo] or 2-chloro-9-(2-deoxy-2,2-
difluoro-beta-D-ribofuranosyl)adenine [CI-diF(up arrow down arrow)-dAdo]. T
he compounds were similar as substrates of deoxycytidine kinase. Similar am
ounts of their respective triphosphates accumulated in CEM cells, and the r
ate of disappearance of these metabolites was also similar. CI-F(up arrow)-
dAdo was 10- to 30-fold more potent in its ability to inhibit the incorpora
tion of cytidine into deoxycytidine nucleotides than either CI-F(down arrow
)-dAdo or CI-diF(up arrow down arrow)-dAdo, respectively, which indicated t
hat ribonucleotide reductase was differentially inhibited by these three co
mpounds. Thus, the differences in the cytotoxicity of these agents toward C
EM cells were not related to quantitative differences in the phosphorylatio
n of these agents to active forms but can mostly be accounted for by differ
ences in the inhibition of ribonucleotide reductase activity. Furthermore,
the inhibition of RNA and protein synthesis by CI-F(down arrow)-dAdo and CI
-diF(up arrow down arrow)-dAdo at concentrations similar to those required
for the inhibition of DNA synthesis can help explain the poor antitumor sel
ectivity of these two agents because all cells require RNA and protein synt
hesis.