ENHANCED METABOLISM OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN DOWN-SYNDROME CELLS - A CONTRIBUTING FACTOR TO THE SUPERIOR EVENT-FREE SURVIVALOF DOWN-SYNDROME CHILDREN WITH ACUTE MYELOID-LEUKEMIA

Down syndrome (DS) children with acute myeloid leukemia (AML) have sig nificantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-beta-D-arabinofuran osylcytosine (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. D S myeloblasts were approximately 10-fold more sensitive to ara-C (meas ured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bro mide (MTT) colorimetric sensitivity assay), compared with non-DS myelo blasts, following exposure to ara-C for 72 hours. Mean levels of 1-bet a-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significan tly higher in DS myeloblasts compared with non-DS myeloblasts after in cubation with 5 mu mol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cel l lines also generated higher levels of ara-CTP compared with cell lin es with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 13 7.6 v 41.7 pmol/mg protein at 1 and 5 mu mol/L ara-C, respectively). E levated ara-CTP levels in the DS cells were accompanied by slightly lo wer levels of endogenous deoxycytidine triphosphate (dCTP) pools, slig htly greater extent of ara-C incorporation into DNA, and increased rel ative numbers of double strand DNA strand breaks. There were no signif icant differences in the cell cycle distributions of DS and non-DS cel ls. These in vitro studies support our hypothesis that enhanced metabo lism 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 cystathio nine-beta-synthase. Further study of the mechanisms tie, alterations i n dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients. (C) 1996 by The American Society o f Hematology.