title: Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells.
abstract: Overexpression of the detoxifying enzyme cytidine deaminase (CDD) renders normal and leukemic hematopoietic cells resistant to cytarabine (1-beta-D-arabinofuranosylcytosine), and studies on murine cells have suggested transgenic CDD overexpression as a way to reduce the substantial myelotoxicity induced by the deoxycytidine analogs cytarabine and gemcitabine (2',2'-difluorodeoxycytidine). We now have investigated CDD (over-)expression in the human hematopoietic system. Retroviral gene transfer significantly increased the resistance of CDD-transduced cord blood and peripheral blood-derived progenitor cells for doses ranging from 20-100 nM cytarabine and 8-10 nM gemcitabine. Protection was observed for progenitors of erythroid as well as myeloid differentiation, though the degree of protection varied for individual drugs. In addition, significant selection of CDD-transduced cells was obtained after a 4-day culture in 30-100 nM cytarabine. Thus, our data demonstrate that overexpression of CDD cDNA results in significant protection of human progenitors from cytarabine- as well as gemcitabine-induced toxicity, and allows in vitro selection of transduced cells. This strongly argues for a potential therapeutic role of CDD gene transfer in conjunction with dose-intensive cytarabine- or gemcitabine-containing chemotherapy regimen.
authors.affiliation: Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Bardenheuer
authors.forename: K
authors.initials: K
authors.lastname: Lehmberg
authors.forename: I
authors.initials: I
authors.lastname: Rattmann
authors.forename: A
authors.initials: A
authors.lastname: Brueckner
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.forename: U R
authors.initials: UR
authors.lastname: Sorg
authors.forename: S
authors.initials: S
authors.lastname: Seeber
authors.forename: T
authors.initials: T
authors.lastname: Moritz
authors.forename: M
authors.initials: M
authors.lastname: Flasshove
mesh_terms: D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D000093542:Gemcitabine
chemical_list: D003561:Cytarabine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine