Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia.
Nuclear factor kappaB (NF-kappaB) 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-kappaB in human T-cell lymphotrophic virus I-infected T cells. We report that the proteasome inhibitor PS-341 decreased NF-kappaB DNA binding activity by preventing degradation of IkappaB(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.
Tan
Chalet
C
Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374, USA.
Waldmann
Thomas A
TA
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000077561:Daclizumab; D004357:Drug Synergism; D006801:Humans; D020672:I-kappa B Proteins; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007074:Immunoglobulin G; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011480:Protease Inhibitors; D011719:Pyrazines; D017452:Receptors, IgG; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D000077561:Daclizumab; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex