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Cystathionine-ß-Synthase cDNA Transfection Alters the Sensitivity and Metabolism of 1-ß-D-Arabinofuranosylcytosine in CCRF-CEM Leukemia Cells in Vitro and in Vivo: A Model of Leukemia in Down Syndrome¹

Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan [J. W. T., M. L. S., Y. R.], Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute [J. W. T., X. H., Y. G. R. M. M., Y. R., L. H. M.], and Departments of Pediatrics [J. W. T., Y. R.], Pharmacology [L. H. M.], and Internal Medicine [J. A. D., R. M. M.], Wayne State University School of Medicine, Detroit, Michigan 48201

The significantly higher event-free survival rates of Down syndrome (DS) children with acute myeloid leukemia compared with non-DS children is linked to increased sensitivity of DS myeloblasts to 1-ß-D-arabinofuranosylcytosine (ara-C) and the enhanced metabolism of ara-C to ara-C triphosphate (J. W. Taub et al., Blood, 87: 3395–3403, 1996). The cystathionine-ß-synthase (CBS) gene (localized to chromosome 21q22.3) may have downstream effects on reduced folate and S-adenosylmethionine pathways; ara-C metabolism and folate pools are linked by the known synergistic effect of sequential methotrexate and ara-C therapy. We have shown that relative CBS transcripts were significantly higher in DS compared with non-DS myeloblasts, and CBS transcript levels correlated with in vitro ara-C sensitivity (J. W. Taub et al., Blood, 94: 1393–1400, 1999). A leukemia cell line model to study the relationship of the CBS gene and ara-C metabolism/sensitivity was developed by transfecting CBS-null CCRF-CEM cells with the CBS cDNA. CBS-transfected cells were a median 15-fold more sensitive in vitro to ara-C compared with wild-type cells and generated 8.5-fold higher [³H]ara-C triphosphate levels after in vitro incubation with [³H]ara-C. Severe combined immunodeficient mice implanted with CBS-transfected CEM cells demonstrated greater responsiveness to therapy, reflected in significantly prolonged survivals after ara-C administration compared with mice implanted with wild-type cells and treated with the same dosage schedule. The transfected cells also demonstrated increased in vitro and in vivo sensitivity to gemcitabine. Deoxycytidine kinase (dCK) activity was approximately 22-fold higher in transfected CEM cells compared with wild-type cells. However, levels of dCK transcripts on Northern blots and protein levels on Western blots were nearly identical between CBS-transfected and wild-type cells. Collectively, these results suggest a posttranscriptional regulation of dCK in CBS-overexpressing cells that contributes to increased ara-C phosphorylation and drug activity. Further elucidating the mechanisms of increased sensitivity of DS cells to ara-C related to the CBS gene may lead to the application of these novel approaches to acute myeloid leukemia therapy for non-DS patients.

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