Direct Relationship of Marrow Cell Growth and 1-β-D-Arabinofuranosylcytosine Metabolism

To define the relationship between perturbed celt growth and intracellular metabolism of 1-β-S-o-arabinofuranosylcytosine (ara-C) in sensitive human cells, growth kinetic, and biochemical pharmacological determinants were examined in normal human bone marrow populations in vitro in normal serum and in the presence of drug-induced humoral stimulatory activity (HSA). Cells cultured in HSA demonstrated both increased proliferation and greater ara-C-related inhibition of DNA synthesis than did cells maintained in normal serum, as measured by [*H]thymidine incorporation into DNA and [3H]thymkJine granulocyte precursor labeling index. Parallel measurements of pH]ara-C incorporation into DNA demonstrated similar behavior in HSA-perturbed cells. When these cultured cells were exposed to 1 and 10 H*A ara-C, intracellular formation of 1-β -o-arabinofuranosycytosine 5'-tri-phosphate over 3 hr and retention of this active form during 1 subsequent hr in drug-free medium were both increased in HSA-stimulated cells relative to cells cultured in normal serum.These studies demonstrate coupling of induced ceN growth kinetics with enhanced intracellular metabolism of the S-phase-specific antimetabolite ara-C in normal human marrow cells. The close direct relationship between growth kinetic perturbation and augmentation of intracellular ara-C activation in this normal hematopoietic model provides a basis for comparison with leukemic cell populations, in which uncoupling of growth kinetics and pharmacokinetics may signify divergence from normal drug-sensitive cell behavior and, thus, resistance to ara-C cytotoxicity.