Although the mechanism of action responsible for the effects of low-dose
ara-C remains unclear, certain insights are available concerning the interaction of this agent with
DNA.
Ara-C incorporates into
DNA, and the extent of (
ara-C)
DNA formation correlates significantly with loss of clonogenic survival. The inhibition of DNA replication by
ara-C also results in DNA fragmentation and terminal differentiation of leukemic cells. Other studies have demonstrated that inhibition of DNA replication by
ara-C results in an aberrant form of
DNA synthesis with certain segments of
DNA being replicated more than once within a single cell cycle. The additional copies of certain segments of
DNA could lead to the accumulation of
DNA fragments and alterations in gene expression. It is of interest that other inhibitors of S-phase DNA replication such as
aphidicolin and
hydroxyurea can also induce similar phenotypic changes in HL-60 and K562
leukemia cells. Although the in vitro data support the concept that
ara-C is capable of inducing leukemic cell differentiation, there is no evidence to suggest that this agent induces differentiation of human leukemic cells in vivo.
Drug levels achieved by administration of low-dose
ara-C (42-64 nmol/L) result in the incorporation of
ara-C into bone marrow mononuclear preparations from patients with
preleukemia syndromes. This concentration of
ara-C (5 X 10(-8) mol/L) slows DNA replication of human leukemic cells in vitro. Thus, the clinical use of low doses of
ara-C that achieve plasma concentrations of 10(-8) to 10(-7) mol/L could theoretically induce maturational effects by partially inhibiting
DNA synthesis. At the present time we have no available data to support this contention. On the basis of chromosomal analyses, low-dose
ara-C apparently maintains sufficient
drug levels to suppress more "malignant" clones, but even "clonal" selection may represent elimination of leukemic cells by either cytotoxicity or induction of terminal differentiation. Further studies will be necessary to define the mechanism of action of low-dose
ara-C in
preleukemia.