Abstract
The action of 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) on DNA synthesis was evaluated both in whole cells and in vitro. 9-β-D-Arabinofuranosyl-2-fluoroadenine was converted to its 5′-triphosphate 9-β-D-arabinofuranosyl-2-fluoroadenine5′-triphosphate (F-ara-ATP) in cells and then incorporated into DNA in a self-limiting manner. More than 94% of the analogue was incorporated into DNA at the 3′ termini, indicating a chain termination action. In vitro DNA primer extension experiments further revealed that F-ara-ATP competed with dATP for incorporation into the A site of the extending DNA strand. The incorporation of F-ara-AMP into DNA resulted in termination of DNA strand elongation. Human DNA polymerase α incorporated more F-ara-AMP into DNA than polymerase ∈ (proliferating cell nuclear antigen-independent DNA polymerase δ) and was more sensitive to inhibition by F-ara-ATP. On the other hand, DNA polymerase ∈ was able to excise the incorporated F-ara-AMP from DNA in vitro. The incorporation of F-ara-AMP into DNA was linearly correlated both with inhibition of DNA synthesis and with loss of clonogenicity; thus it may be the mechanism of cytotoxicity.
Original language | English (US) |
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Pages (from-to) | 16617-16625 |
Number of pages | 9 |
Journal | Journal of Biological Chemistry |
Volume | 265 |
Issue number | 27 |
State | Published - Sep 25 1990 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology