Myeloprotection from the toxic effects of anticancer drugs may permit repeated courses of dose-intensified chemotherapy, and ultimately more effective treatment for patients with cancer. An adeno-associated virus (AAV)-based vector, CWRSP-NDR, was constructed encoding the minimal open reading frame of the human multidrug resistance gene (MDRI), which encodes a 170 kDa transmembrane pump (P-glycoprotein) conferring cellular resistance to a subset of commonly used chemotherapeutic agents. AAV-based vectors are highly promising vehicles for gene therapy because of their high transduction efficiencies, lack of cytopathogenicity, stable integration, and ability to transduce nonproliferating cellular targets. Primary CD34+ cells, a population enriched for hematopoietic progenitors, were isolated from 6 patients and transduced with CWRSP-MDR. Transduction efficiencies of 50-70% (range 20-100%) were noted, with augmented P- glycoprotein expression as determined by both antigenic and functional assays. In this proposal we will extend these important findings to determine consequences of CWRSP-MDR transduction upon the developmental potential of hematopoietic progenitors in vitro, analyze vector integration, P-glycoprotein expression, and ability to select transduced human hematopoietic progenitors in vitro and murine progenitors in an in vivo model, and address safety issues of transplantation with CWRSP-NDR transduced progenitors. These studies may form the groundwork for a gene transfer approach for more effective cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071947-03
Application #
2712819
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
1996-08-01
Project End
2000-05-31
Budget Start
1998-06-11
Budget End
1999-05-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
City of Hope National Medical Center
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010