Direct relationship of marrow cell growth and 1-beta-D-arabinofuranosylcytosine metabolism

Journal Article · Thu Nov 01 04:00:00 EST 1984 · Cancer Res.; (United States)

OSTI ID:5886915

Karp, J E; Donehower, R C; Dole, G B; Burke, P J

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 (/sup 3/H)thymidine incorporation into DNA and (/sup 3/H)thymidine granulocyte precursor labeling index. Parallel measurements of (/sup 3/H)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.

• Research Organization: Johns Hopkins Oncology Center, Baltimore, MD
• OSTI ID: 5886915
• Journal Information: Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 44:11; ISSN CNREA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMAL CELLS
ANIMALS
AZINES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
BONE MARROW CELLS
CELL PROLIFERATION
CONNECTIVE TISSUE CELLS
CYTOSINE
DNA REPLICATION
GROWTH
HEMATOPOIETIC SYSTEM
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LEUKOCYTES
MAMMALS
MAN
MATERIALS
METABOLISM
NUCLEIC ACID REPLICATION
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PRECURSOR
PRIMATES
PYRIMIDINES
REACTION KINETICS
RIBOSIDES
SOMATIC CELLS
THYMIDINE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES