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Direct Relationship of Marrow Cell Growth and 1-ß-D-Arabinofuranosylcytosine Metabolism¹

The Cell Proliferation and Pharmacology Laboratories, The Johns Hopkins Oncology Center, Baltimore, Maryland 21205

To define the relationship between perturbed cell growth and intracellular metabolism of 1-ß-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 µM ara-C, intracellular formation of 1-ß-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.

¹ This work was supported in part by USPHS Grant CA-06973.

² To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 21205.

Received 4/30/84. Accepted 8/ 3/84.

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