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[Cancer Research 62, 1083-1086, February 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Proteasome Inhibitor PS-341, a Potential Therapeutic Agent for Adult T-Cell Leukemia

Chalet Tan and Thomas A. Waldmann1

Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374

Nuclear factor {kappa}B (NF-{kappa}B) plays a major role in the pathogenesis of human T-cell lymphotrophic virus I-associated malignancy. Proteasome inhibitors provide a rational approach to control constitutively activated NF-{kappa}B in human T-cell lymphotrophic virus I-infected T cells. We report that the proteasome inhibitor PS-341 decreased NF-{kappa}B DNA binding activity by preventing degradation of I{kappa}B{alpha}. In our murine model of adult T-cell leukemia, PS-341 used alone did not yield prolongation of the survival of tumor-bearing mice. However, when combined with the current clinically approved drug humanized anti-Tac, therapy with PS-341 was associated with a complete remission in a proportion of treated animals, whereas only a partial response was observed in animals treated with humanized anti-Tac alone.




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