However, this is not the
case with dCTP, which appeared to act as a competitive inhibitor
of the phosphate donor (ATP) and as a noncompetitive inhibitor of the phosphate acceptor (deoxycytidine or cytosine intracellular pool of these deoxynucleotides should be more rearabinoside).
These results could be explained if one assumes sistant to cytosine arabinoside.
that there is a second site of inhibition of dCTP. Although the
inhibition produced by dCTP appeared to be primarily competi- Acknowledgments-We wish to thank Mrs. Joyce Cramer and
tive with the phosphate donor, it is possible that the inhibition Mrs. Barbara Morcaldi for their excellent technical assistance.
may have been also weakly competitive with the phosphate acceptor,
cytosine arabinoside being more sensitive to this inhibition
than deoxycytidine. The similarity in structure of
deoxycytidine and dCTP would favor this proposal. This type
of inhibition has been observed by Okazaki and Kornberg (18),
who reported that dTTP appeared to act as a competitive inhibitor
of the phosphate acceptor (deoxythymidine) of deoxythymidine
kinase of Escherkhiu coli.
In kinetic studies with deoxycytidine kinase, it was found that
both deoxycytidine and cytosine arabinoside were competitive
inhibitors of each other. However, deoxycytidine was a much
more potent competitive inhibitor than cytosine arabinodide.
This result is probably due to the greater afhnity of deoxycytidine
for the phosphate acceptor site than cytosine arabinoside
and to the phosphorylation and release of cytosine arabinoside
from the acceptor site, thus making this site more accessible to
deoxycytidine.
The data presented in this paper suggest that the reversal by
deoxycytidine of the inhibitory effects produced by cytosine
arabinoside on mammalian cells (3, 7) must involve to some extent
interactions with deoxycytidine kinase. The competitive
inhibition of the phosphorylation of cytosine arabinoside by
deoxycytidine and the inhibition of deoxycytidine kinase by
cytosine deoxynucleotides (8, 9) would result in a decreased conversion
of cytosine arabinoside to its active form. The increased
sensitivity of cytosine arabinoside to the inhibitory effects of
cytosine deoxynucleotides suggests that tumor cells with a larger