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.
Uckun
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FM
Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine and Developmental Therapeutics Program, Children's Hospital Los Angeles, Los Angeles, California 90027-0367, USA. fmuckun@chla.usc.edu
Dibirdik
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I
Qazi
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D000818:Animals; D005260:Female; D006801:Humans; D051379:Mice; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D007938:Leukemia / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D010793:Phthalazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D000072377:Syk Kinase; D014916:Whole-Body Irradiation
D047908:Intracellular Signaling Peptides and Proteins; C043388:phthalazine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011838:Radiation-Sensitizing Agents; D000072377:Syk Kinase; C000606896:SYK protein, human; C000606897:Syk protein, mouse; C000715707:(SYK) inhibitor C61