title: 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.
abstract: 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.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit 48201, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Taub
authors.forename: L H
authors.initials: LH
authors.lastname: Matherly
authors.forename: M L
authors.initials: ML
authors.lastname: Stout
authors.forename: S A
authors.initials: SA
authors.lastname: Buck
authors.forename: J G
authors.initials: JG
authors.lastname: Gurney
authors.forename: Y
authors.initials: Y
authors.lastname: Ravindranath
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D018572:Disease-Free Survival; D004314:Down Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D004854:Herpesvirus 4, Human; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D012075:Remission, Spontaneous; D015996:Survival Rate
chemical_list: D003845:Deoxycytosine Nucleotides; D003561:Cytarabine; D006710:Homocysteine; D001085:Arabinofuranosylcytosine Triphosphate; C024107:2'-deoxycytidine 5'-triphosphate; D003541:Cystathionine beta-Synthase; D008727:Methotrexate