Gene transfer of multidrug resistance into a factor-dependent human
hematopoietic progenitor cell line: in vivo model for genetically
transferred chemoprotection
P Schwarzenberger, S Spence, N Lohrey, T Kmiecik, DL Longo, WJ Murphy, FW Ruscetti and JR Keller
Laboratory of Leukocyte Biology, National Cancer Institute-Frederick Cancer
Research and Development Center, MD, USA.
To develop a rapid preclinical in vivo model to study gene transfer into
human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were
infected with multidrug resistance (MDR1)-containing retroviruses and then
transplanted into nonobese diabetic severe combined immunodeficient mice
(NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1
cDNA showed integration, transcription, and expression of the transfered
MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e
cells to paclitaxel in vitro. The expression of the MDR1 gene product was
stable over a 6-month period in vitro without selection in colchicine.
MO-7e and MDR1-infected MO-7e cells were transplanted into NOD SCID mice to
determine whether MDR1 could confer drug resistance in vivo. A sensitive
polymerase chain reaction method specific for human sequences was developed
to quantitate the level of human cell engraftment in NOD SCID bone marrow
(BM) cells. The percentage of human DNA in BM cells from MO-7e-
transplanted mice was 10.9% and decreased to 0.7% in mice treated with
paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice
was 7.6% and that level was unchanged in mice treated with paclitaxel.
These results show that expression of the MDR1 gene in human hematopoietic
progenitor cells can confer functional drug resistance in an in vivo model.
Volume 87,
Issue 7,
pp. 2723-2731,
04/01/1996
Copyright © 1996 by The American Society of Hematology
