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Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome
cells: a contributing factor to the superior event free survival of Down
syndrome children with acute myeloid leukemia
JW Taub, LH Matherly, ML Stout, SA Buck, JG Gurney and Y Ravindranath
Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan,
Detroit 48201, USA.
Down syndrome (DS) children with acute myeloid leukemia (AML) have
significantly higher event-free survival (EFS) rates compared with non- DS
children when treated with protocols containing 1-beta-D-
arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was
examined in myeloblasts from DS and non-DS patients with AML, DS infants
with the transient myeloproliferative disorder, and Epstein- Barr Virus
(EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS
myeloblasts were approximately 10-fold more sensitive to ara-C (measured by
the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT)
colorimetric sensitivity assay), compared with non-DS myeloblasts,
following exposure to ara-C for 72 hours. Mean levels of
l-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were
significantly higher in DS myeloblasts compared with non-DS myeloblasts
after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein).
DS cell lines also generated higher levels of ara-CTP compared with cell
lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and
137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively).
Elevated ara-CTP levels in the DS cells were accompanied by slightly lower
levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly
greater extent of ara-C incorporation into DNA, and increased relative
numbers of double strand DNA strand breaks. There were no significant
differences in the cell cycle distributions of DS and non-DS cells. These
in vitro studies support our hypothesis that enhanced metabolism of ara-C
in DS cells may be a contributing factor to the superior survival rate of
DS children with AML and is possibly based on a gene dosage effect of genes
localized to chromosome 21 including cystathionine-beta-synthase. Further
study of the mechanisms (ie, alterations in dCTP pools and DNA methylation)
involved may lead to improvements in the treatment of all AML patients.
Volume 87,
Issue 8,
pp. 3395-3403,
04/15/1996
Copyright © 1996 by The American Society of Hematology
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