科研之友
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摘要
Purpose: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-kappa B activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-kappa B activity in blood (if possible tumor), and characterizing antitumor activity. Experimental Design: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m(2)) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m(2)) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-kappa B biomarker activity. Results: Bortezomib (1.3 mg/m(2)) and temozolomide (75 mg/m(2)) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease >= 4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-kappa B electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome. Conclusions: We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-kappa B activation. Clin Cancer Res; 16(1); 348-57.
- 出版日期2010-1-1
