Direct relationship of marrow cell growth and 1-beta-D-arabinofuranosylcytosine metabolism.
To define the relationship between perturbed cell growth and intracellular metabolism of 1-beta-D-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 [3H]thymidine incorporation into DNA and [3H]thymidine granulocyte precursor labeling index. Parallel measurements of [3H]ara-C incorporation into DNA demonstrated similar behavior in HSA-perturbed cells. When these cultured cells were exposed to 1 and 10 microM ara-C, intracellular formation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate 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 cell 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.
D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology; D004261:DNA Replication; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D013936:Thymidine / Q000378:metabolism*; D014316:Tritium
D003561:Cytarabine; D014316:Tritium; D013936:Thymidine