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Mechanisms of Cell Death of Chronic Lymphocytic Leukemia Lymphocytes by RNA-Directed Agent, 8-NH₂-Adenosine

Authors' Affiliations: Departments of ¹ Experimental Therapeutics and ² Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Varsha Gandhi, Department of Experimental Therapeutics, Unit 71, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. Phone: 713-792-2989; Fax: 713-794-4316; E-mail: vgandhi{at}mdanderson.org.

Purpose: To determine if RNA-directed nucleoside analogue, 8-NH₂-adenosine, induces cell death and if that is accompanied with transcription inhibition of the key survival factors of chronic lymphocytic leukemia (CLL) cells.

Experimental Design: Primary lymphocytes from CLL patients were incubated with 10 µmol/L 8-NH₂-adenosine for 2, 4, and 6 or 8 hours. The accumulation of analogue triphosphate and the decline in endogenous ATP pool were analyzed by high-performance liquid chromatography. Inhibition of global RNA and protein synthesis was measured and correlated with specific decline in transcript and protein levels of MCL-1, XIAP, and BCL-2, the key survival factors of CLL. These biochemical and molecular end points were related to cell death of these quiescent lymphocytes.

Results: In vitro incubations of CLL lymphocytes with 8-NH₂-adenosine resulted in rapid but heterogeneous accumulation of 8-NH₂-ATP (390-680 µmol/L), with a concomitant decline in endogenous ATP (median, >50% by 4 hour). Global RNA synthesis was decreased in all samples and was associated with a decline in MCL-1, XIAP, and BCL-2 transcripts. There was a parallel decrease in the protein level of MCL-1 and XIAP but not BCL-2. These biochemical changes were accompanied by apoptosis.

Conclusion: The evidence of CLL cell death with complementary changes in the expression of survival proteins provides a molecular rationale for using 8-NH₂-adenosine as a therapeutic agent for this indolent leukemia.

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