In these transduced cells, procathepsin L secretion was strongly inhibited. In addition, injection of this anti-cathepsin L-ScFv Ispinesib ic50 lentiviral vector into tumors already induced in nude mice, inhibits tumor progression and associated angiogenesis. This is the first report to demonstrate that targeting procathepsin L secretion with anti-cathepsin L-ScFv lentiviral construct constitutes a new gene therapy to inhibit the progression of tumors induced by human melanoma cells. O125 Disruption
of Leukemia/Stroma Cell Interactions by CXCR4 Antagonists Enhances Chemotherapy and Signal Transduction-Induced Apoptosis in Leukemias Michael Andreeff 1 , Zhihong Zeng1, Michael Fiegl1, Marina Konopleva1 1 Molecular Hematology & Therapy, Departments SGC-CBP30 price of Stem Cell Transplantation & Cellular Therapy and Leukemia, UT M. D. Anderson Cancer Center, Houston, TX, USA The see more chemokine receptor CXCR4 is critically involved in the migration of hematopoietic cells to the stroma-derived-factor-1α (SDF-1a)-producing bone marrow microenvironment. We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva, Leukemia 16:1713, 2002). Inhibition of CXCR4 with a specific peptide abrogated this effect and sensitized leukemic
cells to chemotherapy (Zeng et al. MCT 5, 3113, 2006). Importantly, CXCR4 is upregulated by physiological hypoxia in the bone marrow (Fiegl et al. BLOOD, 113:1504, 2009) and contributes to pro-survival signaling in hematopoietic cells, through PI3K/AKT, MAPK and STAT3 signaling. AMD3465, a second generation small-molecule CXCR4 inhibitor with Thiamet G greater potency than AMD3100 (Plerixafor) was used to test the hypothesis that CXCR4 inhibition
disrupts stromal/leukemia cell interactions and overcomes stroma-mediated resistance. Results show that AMD3465 inhibits surface expression of CXCR4 on AML cells and SDF-1a and stroma (MS-5)-induced migration of leukemia cells. In vitro, stromal cells protect leukemic cell lines and primary AML cells from spontaneous, chemotherapy, and tyrosine kinase (TKI) inhibitor-induced apoptosis. CXCR4 inhibition enhanced Ara-C-, Busulfan- and Sorafenib- (FLT3-ITD inhibitor) induced apoptosis and, importantly, downregulated AKT and MAPK signaling. In vivo xenografts into (NOD/SCID/IL-2Rα-1-) mice and syngeneic (Ba/F3-ITD) leukemia models showed even more pronounced effects, resulting in mobilization of leukemia stem cells and much enhanced efficacy of Ara-C and Sorafenib (Zeng et al. BLOOD, e-pub Oct 2008). In patients with AML in CR, treatment with AMD3100+G-CSF mobilized up to 80% leukemic cells into circulation. Conclusion: Data suggest that SDF-1a/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy and TKI-induced apoptosis.