title: Multidrug resistance 1 gene transfer can confer chemoprotection to human peripheral blood progenitor cells engrafted in immunodeficient mice.
abstract: Myelosuppression is the main side effect of cancer chemotherapy. An improved rate of retroviral vector-mediated gene transfer to hematopoietic stem cells, shown in more recent clinical trials, has created the basis to test the concept of myeloprotective gene therapy. We transplanted clinical-scale human peripheral blood progenitor cell grafts (n = 2) transduced with retroviral vector SF91m3, which contains the human multidrug resistance 1 gene (MDR1), into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Engrafted mice of one cohort were protected from paclitaxel toxicity (p < 0.05) and we noted a similar trend in the second cohort. In paclitaxel-treated mice that had received gene-transduced cells we found a significant increase in gene marking (p < 0.05 - p < 0.01) or P-glycoprotein expression (p < 0.01) compared with their chemotherapy-naive counterparts. This is the first report showing that cytostatic drug resistance gene therapy can mediate chemoprotection of human clinically relevant stem cell populations with marrow engraftment potential.
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schiedlmeier
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Schilz
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Stephanie
authors.initials: S
authors.lastname: Laufs
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: W Jens
authors.initials: WJ
authors.lastname: Zeller
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Eckert
authors.forename: Stefan
authors.initials: S
authors.lastname: Fruehauf
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004351:Drug Resistance / Q000235:genetics; D018014:Gene Transfer Techniques; D019450:Genes, MDR / Q000235:genetics*; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D017239:Paclitaxel