Comparative in-Vitro Evaluation of the Myeloid Toxicity of Pentostatin and the Novel PNP-Inhibitor Forodesine.

Abstract 3766 Poster Board III-702 Inhibitors of the purine metabolism show promising results in the treatment of lymphatic malignancies due to their suppressive effects on lymphogenesis. Their first representative, Pentostatin (Pento), an inhibitor of the deoxyadenosine deaminase, has been in clinical use for several decades. However, early clinical trials with higher dose ranges of the drug reported unforseen severe myelotoxic effects. Recently, Forodesine (Foro), a novel inhibitor of the nucleoside phosphorylase (PNP) has been introduced and is currently deployed in clinical phase I/II trials for the treatment of acute lymphatic leukemia (ALL). In order to systematically evaluate the myelotoxic effects of Pento and Foro, we have now examined their influence on the proliferation and differentiation of primitive and lineage committed hematopoietic progenitor cells (HPCs). In vitro dose/effect-curves for Foro, Pento, and Cytarabine (AraC) were generated for the leukemic cell line jurkat by 48 hours of co-incubation with the compounds. Adequate cytotoxic effects, measured in the XTT assay and by flow cytometric analysis, were observed in clinically relevant dose ranges. For the following studies, an equivalent IC 60 dose of each chemotherapeutic agent was selected and CD34+ HPCs from either bone marrow, mobilized peripheral blood, or umbilical cord blood were incubated with the compounds for 48 hours. Subsequently, the rate of vital cells was determined by flow cytometry after stainig with Annexin-V and Propidium Iodide. Compared to the untreated control, the lowest amount of vital CD34+ cells was found in AraC-treated samples (30%); Foro and Pento yielded more vital cells (66% vs 61%). The combination of Foro and Pento unexpectedly had the least toxic effect on CD34+ cells (72%; n=5; p Disclosures: Schubert: Mundipharma Int. LTD: Research Funding.