{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:01:52Z","timestamp":1791270112627,"version":"4.1.0"},"reference-count":29,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2002,11,15]]},"abstract":"<jats:p> PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies. <\/jats:p><jats:p> PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg\/m<jats:sup>2<\/jats:sup>, followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity. <\/jats:p><jats:p> RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg\/m<jats:sup>2<\/jats:sup> MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and\/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease. <\/jats:p><jats:p> CONCLUSION: PS-341 was well tolerated at 1.04 mg\/m<jats:sup>2<\/jats:sup> on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose\/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin\u2019s lymphoma in this study, and merits further investigation in these populations. <\/jats:p>","DOI":"10.1200\/jco.2002.01.133","type":"journal-article","created":{"date-parts":[[2002,11,14]],"date-time":"2002-11-14T00:41:13Z","timestamp":1037234473000},"page":"4420-4427","source":"Crossref","is-referenced-by-count":619,"title":["Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies"],"prefix":"10.1200","volume":"20","author":[{"given":"Robert Z.","family":"Orlowski","sequence":"first","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Stinchcombe","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly S.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Shea","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert S.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Stahl","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Adams","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dixie-Lee","family":"Esseltine","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Elliott","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine S.","family":"Pien","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Guerciolini","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Anderson","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie D.","family":"Depcik-Smith","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Bhagat","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Jo","family":"Lehman","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Novick","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Soignet","sequence":"additional","affiliation":[{"name":"From the Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology\/Oncology, Department of Biology, and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Millennium Pharmaceuticals, Inc, Cambridge, MA; and the Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center and the Joan and Sanford Weill Medical College of Cornell University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1-116100","unstructured":"Goldberg  AL,   Akopian  TN,   Kisselev  AF,  et al:   New insights into the mechanisms and importance of the proteasome in intracellular protein degradation.  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