The objectives of this grant are to transfer and express the human multiple drug resistance (MDR) gene in CD34+ hematopoietic progenitor cells (HPCs) of patients with advanced breast cancer using a safe and efficient retrovirus. The projected result of this treatment is that MDR-transduced cells will ameliorate myelosuppression of subsequent chemotherapy with drugs that are inactivated by MDR (anthracyclenes, vinca alkaloids, etoposide and taxol). Normal HPCs have low levels of MDR activity and are, therefore, preferentially sensitive to these drugs. If successful, this program would add a novel modality to the treatment of patients with advanced breast cancer as well as address questions of the relative contributions of marrow, peripheral blood progenitor cells (PBPCs) and endogenous hematopoiesis to marrow recovery. Subsequent studies would evaluate higher dose single agent then combination chemotherapy regimens utilizing repetative doses of MDR affected agents. Protocols will be developed and carried out in which MDR gene transfer will be used. The goal of the clinical program is to carry out and monitor this approved protocol and to carry out subsequent phase 1 and 2 protocols developed by the BCTG in collaboration with CTEP. New protocols will focus on transduction of peripheral blood progenitor cells (PBPC) with the best MDR retroviral vectors and optimal conditions for transduction of CD34+ cells. Subsequent studies would exploit these observations by designing and evaluating repeated doses of combinations of MDR affected drugs for patients who have had hematopoietic progenitors transduced with MDR containing retrovirus.
| Bradley, M Brigid; Sattler, Rose M; Raftopoulos, Harry et al. (2002) Correction of phenotype in a thalassemia mouse model using a nonmyeloablative marrow transplantation regimen. Biol Blood Marrow Transplant 8:453-61 |
| Lopez, Rocio A; Schoetz, Stuti; DeAngelis, Kathryn et al. (2002) Multiple hematopoietic defects and delayed globin switching in Ikaros null mice. Proc Natl Acad Sci U S A 99:602-7 |
| Hesdorffer, C; Ayello, J; Ward, M et al. (1998) Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation. J Clin Oncol 16:165-72 |
