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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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.

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.[1]


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