The objective of this research project is to delineate the mechanism(s) underlying the mobilization of CD34+ stem cell subsets in patients with metastatic breast cancer undergoing autologous bone marrow transplantation at the University of Rochester. Emerging results from our Center and several other groups have indicated that the inclusion of mobilized progenitors obtained after growth factor treatment hastens the engraftment process and decreases the costs and morbidity of the transplantation procedure. To this end we will study patients with stage IV breast cancer enrolled in our protocol T92-OO1O, which is a pilot study aimed at evaluating the efficacy of hematopoietic growth factors in mobilizing peripheral blood CD34+ progenitors. The study will enroll a total of 17 patients in each one of three arms 1) GM-CSF 5 micrograms/kg S.C. alone; 2) G-CSF 5 micrograms/kg S.C. alone and 3) GM-CSF combined with G-CSF each at 2.5 micrograms/kg S.C. daily. We will in the next year add a fourth arm which will be PIXY-321 at 75O micrograms/m2 S.C. daily (protocol amendment pending). Since the extent of peripheral blood stem cell mobilization in our hands as well as others is increased after cyclophosphamide (cytoxan) chemotherapy combined with growth factor administration, patients on either arm will receive 1.5 gm/m2 of cytoxan on two consecutive days prior to growth factor administration. The kinetics of CD34+ subset mobilization will be correlated with in-vitro progenitor assays and in-vivo engraftment data. A major focus of our research will be to develop innovative techniques for the detection of CD34+ cell subsets capitalizing on the expertise in high speed flow cytometry (Dr. James Leary) with positive selection techniques in order to determine as accurately as possible the frequency of cD34+ progenitor subsets in the blood of patients before and after stem cell mobilization. In addition, a major focus of our studies will be to define mechanisms that may underlie efficient progenitor recruitment by measuring adhesive receptors on these mobilized CD34+ cells and correlating the kinetics of progenitor recruitment with cytokine levels (such as IL-1 and IL-1RA, Stem Cell Factor, G-CSF, GM-CSF, TNF- alpha...) during the mobilization process.
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