Augmentation of the Antileukemia Potency of Total-Body Irradiation (TBI) by a Novel P-site Inhibitor of Spleen Tyrosine Kinase (SYK)

A novel spleen tyrosine kinase (SYK) P-site inhibitor, 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C-61), (but not vehicle) markedly enhanced H(2)O(2)-induced apoptosis of primary leukemia cells from each of five relapsed B-lineage acute lymphoblastic leukemia (ALL) patients, as measured by in vitro TUNEL assays. A highly radiation-resistant subclone of the murine B-lineage leukemia cell line BCL-1 was next used to investigate the in vivo radiosensitizing effects of C-61. C-61 enhanced the antileukemia potency of 7 Gy total-body irradiation (TBI) in the context of syngeneic bone marrow transplantation (BMT) at 20% of its nonobservable adverse effect level (NOAEL) that does not exhibit detectable single-agent activity against BCL-1 leukemia in vivo. Based on this preclinical proof-of-principle study, we hypothesize that the incorporation of C-61 into the pretransplant TBI regimens of patients with recurrent or high-risk B-lineage acute lymphoblastic leukemia (ALL) will help overcome the radiochemotherapy resistance of their leukemia cells and thereby improve their treatment response and survival outcome after BMT. (C) 2010 by Radiation Research Society