Modulation of arabinosylcytosine metabolism by arabinosyl-2- fluoroadenine
in lymphocytes from patients with chronic lymphocytic leukemia:
implications for combination therapy
V Gandhi, B Nowak, MJ Keating and W Plunkett
Department of Medical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030.
Our previous studies indicated that K562 cells loaded with arabinosyl-2-
fluoroadenine 5'-triphosphate (F-ara-ATP) accumulated arabinosylcytosine
5'-triphosphate (ara-CTP) at a threefold higher rate compared to the
control cells. In the present study lymphocytes were obtained from patients
with chronic lymphocytic leukemia before and after F-ara-A monophosphate
therapy. The rate of ara-CTP accumulation after in vitro ara-C incubation
was compared in lymphocytes obtained prior to therapy without any other
manipulation, after ex vivo F-ara- ATP (100 mumol/L) treatment, and after
in vivo F-ara-A monophosphate therapy. Lymphocytes showed a 2.2-fold (n =
23) and 1.7-fold (n = 23) median increase in the cellular concentration of
ara-CTP after an ex vivo incubation with 100 mumol/L F-ara-A and 20 to 24
hours after the first dose (25 or 30 mg/m2) of F-ara-A monophosphate in
vivo treatment, respectively. Although the rates of F-ara-ATP and ara-CTP
accumulation varied among patients, a relationship was observed in
individuals between the cellular concentration of F-ara-ATP at the
beginning of the ara-C incubation and ara-CTP accumulation. These studies
strongly suggest that a protocol designed to administer F-ara-A
monophosphate prior to ara-C infusion will augment ara-CTP accumulation by
leukemia cells.
Volume 74,
Issue 6,
pp. 2070-2075,
11/01/1989
Copyright © 1989 by The American Society of Hematology
