Proteasome Inhibition With Bortezomib (PS-341): A Phase I Study With Pharmacodynamic End Points Using a Day 1 and Day 4 Schedule in a 14-Day Cycle

Hamilton, Anne; Eder, Joseph P.; Pavlick, Anne C.; Clark, Jeffrey W.; Liebes, Leonard; Garcia-Carbonero, Rocío; Chachoua, Abraham; Ryan, David P.; Soma, Vikas R; Farrell, Katrina; Kinchla, Nancy M.; Boyden, J.; Yee, H.; Zeleniuch‐Jacquotte, Anne; Wright, John J.; Elliott, Peter J.; Adams, Julian; Fm, Muggia

doi:10.1200/jco.2005.01.136

Cited by 92 publications

(77 citation statements)

References 19 publications

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“…Coadministration of docetaxel with bortezomib did not appear to affect 20S proteasome inhibition by bortezomib. The degree of inhibition observed is similar to that observed in studies of bortezomib monotherapy (Aghajanian et al, 2002;Orlowski et al, 2002;Blaney et al, 2004;Papandreou et al, 2004;Hamilton et al, 2005).…”

Section: Pharmacodynamicssupporting

confidence: 73%

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

et al. 2008

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The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60 -100 mg m À2 on day 1) plus bortezomib (1.0 -1.5 mg m À2 on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n ¼ 1) and febrile neutropenia (n ¼ 4). The MTD was bortezomib 1.5 mg m À2 plus docetaxel 75 mg m À2 . All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/ docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents.

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Section: Pharmacodynamicssupporting

confidence: 73%

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

et al. 2008

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“…7 Moreover, proteasome inhibition by the chemotherapeutic medication bortezomib causes demyelinating neuropathy and worsens the neuropathic symptoms of CMT patients. 21,22 These findings suggest that proteasome dysfunction could contribute to demyelinating CMT pathogenesis.…”

Section: Discussionmentioning

confidence: 90%

Protein misfolding and clearance in demyelinating peripheral neuropathies

Lee

Chin

2012

Communicative & Integrative Biology

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“…Of note, Bortezomib is currently given twice weekly to patients to achieve maximal CT-L inhibition (75 -78%). The CT-L activity inhibition in peripheral blood cells of patients is noted within an hour of Bortezomib administration and recoverable before the next dose (Adams, 2002;Hamilton et al, 2005).…”

mentioning

confidence: 99%

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

2006

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Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/ refractory MM patients. The systemic regulation of protein synthesis and protein degradation is essential for normal cellular functioning. The ubiquitinproteasome pathway mediates intracellular protein degradation: first, protein is marked with a chain of small polypeptides called ubiquitin; E1 ubiquitin enzyme then activates ubiquitin and links it to the ubiquitin-conjugating enzyme E2 in an ATP-dependent manner; E3 ubiquitin ligase then links the ubiquitin molecule to the protein; a long polypeptide chain of ubiquitin moieties is formed; and finally, a multi-enzyme proteolytic complex 26S proteasome degrades protein into small fragments in an ATPdependent manner.

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Proteasome Inhibition With Bortezomib (PS-341): A Phase I Study With Pharmacodynamic End Points Using a Day 1 and Day 4 Schedule in a 14-Day Cycle

Abstract: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Cited by 92 publications

References 19 publications

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

Protein misfolding and clearance in demyelinating peripheral neuropathies

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

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