title: KRN5500: a novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis.
abstract: Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 microM, 0.276 microM, and 0.139 microM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, OH 43210, USA. byrd-3@medctr.osu.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mone
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Kitner
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Drabick
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D011684:Purine Nucleosides; C092296:KRN 5500; D020169:Caspases