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¹ Division of Hematology Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Medical School, Chicago, Illinois and ² Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Nancy L. Krett, Division of Hematology Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Medical School, Chicago, IL 60611. Phone: 312-908-5919; Fax: 312-908-1372. E-mail: n-krett{at}northwestern.edu

Multiple myeloma (MM) is a malignancy of clonal B-cells that accounts for 10% of all hematologic malignancies. We have shown previously that a novel purine analogue, 8-chloro-adenosine, has significant activity for MM in preclinical studies. Objective: Using MM cell lines, we investigated the molecular mechanism of related congener of adenosine, 8-amino-adenosine (8-NH₂-Ado). Methods: We employed biological and biochemical assays in MM cell lines to evaluate the clinical potential of 8-NH₂-Ado. Results: In MM cell lines both sensitive and resistant to conventional chemotherapies, 8-NH₂-Ado is cytotoxic, with IC₅₀ ranging from 300 nmol/L to 3 µmol/L. A mouse leukemic cell line lacking adenosine kinase activity was resistant to 8-NH₂-Ado, indicating that phosphorylation of 8-NH₂-Ado to its triphosphate form is required for cytotoxicity. A 4-hour incubation of MM cells with 10 µmol/L analogue resulted in an accumulation of >7 mmol/L 8-NH₂-ATP with a parallel decline in the endogenous ATP levels. Accumulation of 8-NH₂-ATP was dependent on both exogenous concentration of 8-NH₂-Ado and incubation time. The accumulation of 8-NH₂-ATP was accompanied by a decrease in both RNA and DNA synthesis. The mechanism of 8-NH₂-Ado-mediated cytotoxicity was due to apoptosis as measured by an increase in Annexin V binding, a decrease in mitochondrial membrane potential, an increase in caspase activity, cleavage of caspase substrates, and an increase in cells with a sub-G₁ DNA content. Conclusion: Based on these results, we conclude that 8-NH₂-Ado may hold great potential as a therapeutic agent for the treatment of MM.

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Note: C. Nabhan is currently at Oncology Specialists, S.C., Lutheran General Hospital Cancer Care Center, Park Ridge, IL 60056.

Received 9/15/03; revised 7/13/04; accepted 8/27/04.