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Relationships among Ara-CTP pools, formation of (Ara-C)DNA, and
cytotoxicity of human leukemic cells
D Kufe, D Spriggs, EM Egan and D Munroe
Cytosine arabinoside (Ara-C) is the most effective agent in the treatment
of acute myelogenous leukemia. This agent incorporates in leukemic cell
DNA, and the extent of this incorporation correlates with loss of
clonogenic survival. The incorporated Ara-C residue behaves as a relative
DNA chain terminator, and the extent of (Ara-C)DNA formation correlates
with inhibition of DNA synthesis. The incorporation of Ara-C into DNA
requires the formation of Ara-CTP, and previous measurements of this
metabolite have also been correlated with cytotoxicity. Because it is
clinically relevant to define biochemical parameters predictive of Ara-C
cytotoxicity, the present studies were undertaken to determine the
relationship among Ara-CTP pools, formation of (Ara-C)DNA, and loss of
clonogenic survival. The results demonstrate that the incorporation of
Ara-C into DNA is the single most powerful predictor of cell lethality.
Furthermore, although there is a correlation between Ara-CTP pools or
continuous cellular exposure to Ara-CTP and cell kill, these relationships
are less significant than that obtained with formation of (Ara-C)DNA. The
extent of Ara-C incorporation into DNA can be predicted by the product of
the Ara-CTP level and time (T), thus supporting the concept that Ara-C
incorporation is dependent on continuous exposure to the triphosphate
metabolite. These findings support the formation of (Ara-C)DNA as a highly
predictive parameter of lethal cellular events.
Volume 64,
Issue 1,
pp. 54-58,
07/01/1984
Copyright © 1984 by The American Society of Hematology
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