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Blood, 1 August 2004, Vol. 104, No. 3, pp. 802-809.
Prepublished online as a Blood First Edition Paper on April 15, 2004; DOI 10.1182/blood-2003-11-3967.
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NEOPLASIA
Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants
Shibani Mitra-Kaushik,
John C. Harding,
Jay L. Hess, and
Lee Ratner
From the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO; and the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Recent studies have shown that the transcription factor nuclear factor  B (NF-B) regulates critical survival pathways in a variety of cancers, including human T-cell leukemia/lymphotrophic virus 1 (HTLV-1)–transformed CD4 T cells. The activation of NF-B is controlled by proteasome-mediated degradation of the inhibitor of nuclear factor B (IB). We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in HTLV-1 Tax transgenic tumors in vitro and in vivo. In Tax transgenic mice, PS-341 administered thrice weekly inhibited tumor-associated NF-B activity. Quantitation of proliferation, apoptosis, and interleukin 6 (IL-6) and IL-10 secretion by tumor cells in culture revealed that the effects of PS-341 on cell growth largely correlated with inhibition of pathways mediated by NF-B. However, the effect of PS-341 on the growth of tumors in Tax transgenic mice revealed heterogeneity in drug responsiveness. The tumor tissues treated with PS-341 show no consistent inhibition of NFB activation in vivo. Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to apoptosis induced by  irradiation. On the other hand, transplanted Tax tumors in Rag-1 mice showed consistent inhibition of tumor growth and prolonged survival in response to the same drug regimen. TUNEL staining indicated that PS-341 treatment sensitizes Tax tumors to DNA fragmentation.
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