Multidrug resistance 1 gene transfer can confer chemoprotection to human peripheral blood progenitor cells engrafted in immunodeficient mice

• Published in: Human gene therapy Vol. 13; no. 2; p. 233
• Main Authors: Schiedlmeier, Bernd, Schilz, Andrea J, Kühlcke, Klaus, Laufs, Stephanie, Baum, Christopher, Zeller, W Jens, Eckert, Hans-Georg, Fruehauf, Stefan
• Format: Journal Article
• Language: English
• Published: United States 20-01-2002
• Subjects: Animals; Animals, Genetically Modified; Drug Resistance - genetics; Gene Transfer Techniques; Genes, MDR - genetics; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Mice; Mice, SCID; Paclitaxel - toxicity; Tumor Cells, Cultured
• ISSN: 1043-0342
• DOI: 10.1089/10430340252769761

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.