IN-VIVO EFFECTS OF RECOMBINANT HUMAN STEM-CELL FACTOR TREATMENT - A MORPHOLOGIC AND IMMUNOHISTOCHEMICAL STUDY OF BONE-MARROW BIOPSIES

Bone marrow (BM) aspirate and biopsy specimens from seven female patie nts with advanced or metastatic breast cancer and preserved marrow fun ction treated on a phase I trial of recombinant methionyl human stem c ell factor (r-metHuSCF; SCF) were evaluated by immunohistochemical sta ining before and after treatment with SCF. Doses of SCF included 10 g/ kg/day in 2 patients, 25 mu g/kg/day in 2 patients, and 50 mu g/kg/day in 3 patients administered as subcutaneous bolus injections for 14 da ys. Following treatment, bone marrow cellularity increased up to 1.6-f old (P = NS), with an increased frequency of promyelocytes (P <.002), but an unchanged relative frequency of other marrow hematopoietic cell s. The mean relative frequency of BM CD34+ progenitor cells increased from 0.9% to 1.8% (P <.001). The mean proportion of BM cells stained b y Ki-67/MIB 1 and PCNA/PC10, monoclonal antibodies (MoAb) recognizing proliferation-associated nuclear proteins, increased from 18.6% to 35. 4% (P <.003) and from 32.4% to 49.4% (P <.01), respectively. Most of t he Ki-67 and PCNA positive cells were represented by promyelocytes, pr oerythroblasts, and myeloblasts, SCF therapy was not associated with m arrow fibrosis or increases in the number of macrophages. Peripheral w hite blood cell counts increased 1.3- to 3.6-fold following SCF. The m ean absolute neutrophil counts increased from 3.9 X 10(9)/L (range 2.6 -5.3) to 7.2 X 10(9)/ 1, (range 4.7-12.3), and reticulocyte counts inc reased by a mean of 1,5 fold (range 1.2-fold to 2,0-fold). No consiste nt difference in platelet counts was seen. These results suggest that SCF given in vivo is effective in increasing the frequency of CD34+ BM progenitor cells, and has the capacity to increase the proliferation and differentiation rate of hematopoietic precursor cells. These effec ts indicate that SCF may represent a cytokine capable of affecting mul tiple hematopoietic lineages.