Optimization of multidrug resistance 1 gene transfer confers chemoprotection to human hematopoietic cells engrafted in immunodeficient mice.
OBJECTIVE
To investigate whether an optimization of MDR1 gene transfer protocol would result in stable hematopoietic stem cell (HSC) engraftment and myeloprotection in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice after paclitaxel chemotherapy.


METHODS
We transplanted freshly isolated CD34+ cells or MDR1-transduced CD34+ cells derived from human umbilical cord blood (UCB) into sublethally irradiated NOD/SCID mice. Twenty-eight days after transplantation, mice received paclitaxel chemotherapy and peripheral blood (PB) was collected for analysis of WBC, RBC and PLT counts once every week.


RESULTS
We found that MDR1-transduced human hematopoietic cells could facilitate hematopoietic recovery and completely reconstitute hematopoiesis in mice as well as freshly isolated CD34+ cells. Mice transplanted with MDR1-transduced human hematopoietic cells were protected from paclitaxel chemotherapy with higher survival rate and higher level of WBC counts and RBC counts compared with mice transplanted with untransduced HSCs. We also demonstrated that hematopoietic cells transduced with MDR1 gene were enriched in vivo after paclitaxel chemotherapy determined by the higher percentage of human Rh-123(dull) CD45+ cells in bone marrow of mice.


CONCLUSIONS
Our results demonstrated successful chemoprotection against myelosuppression in mice by MDR1-transduced repopulating human hematopoietic cells with an optimized transduction protocol.
Zhang
Hualing
H
Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University School of Medicine, Jinan, Shandong, China.
Wen
Zeqing
Z
Tan
Shougang
S
Li
Changzhong
C
Lan
Shoumin
S
Li
Jianfeng
J
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects*; D005312:Fetal Blood / Q000637:transplantation*; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D017239:Paclitaxel / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; C421109:multidrug resistance-associated protein 1